October, 2016 Pediatric Heart Network Policy Manual

Transcription

1 October, 2016 Pediatric Heart Network Policy Manual Operational Procedures & Guidelines

2 TABLE OF CONTENTS Pediatric Heart Network Overview Background PHN Mission Statement PHN Organization... 4 PHN Operational Components Steering Committee Executive Committee Publications and Presentations Committee Ancillary Studies Committee Study Coordinators Committee Finance Committee Core Laboratory Selection Committee Biospecimen Committee Oversight of PHN Activities Introduction Protocol Review Committee Data & Safety Monitoring Board Protocol Development and Implementation Study Proposals Protocol Development and Review Study Implementation Quality Assurance Overview Routine Study and Data Quality Checks Site Visits Performance Reports Unblinding Procedures for Trials Publications and Presentations Policy Introduction Objectives Definitions Proposal and Approval Process for Papers, Abstracts and Presentations Selection of Writing Committee Chair and Members for Papers and Abstracts Preparation of Papers Responsibilities of Writing Committee Members Responsibilities of the Study Committee Chair Responsibilities of the PPC Chair Authorship of Papers and Abstracts Clearance and Submission of Papers Submission of Manuscripts to Pub Med Central PAGE 2 OF 73

3 6.10 Preparation, Submission, and Presentation of Abstracts at National and International Meetings Documentation of Publication Process PHN Ancillary Studies and Presentations Dissemination of Information Invitations to PHN Investigators for Presentation of PHN- RelatedInformation Use of PHN Material for Graduate/Medical Student Theses or Dissertations Ancillary Studies Policy Definitions Funding Ancillary Study Philosophy Proposal Process for Ancillary Studies Application and Review Process for Ancillary Studies Review Criteria Publication Considerations (See also Publication and Presentations Policy in Chapter 6) Ancillary Study Checklist for the Main Study Committee Ancillary Studies Involving Biospecimens or Biologic Datasets Conflict of Interest Policies and Procedures A1.1 Financial Conflicts of Interest A1.2 Conflict Resolution Biospecimens Policy and Procedures A2.1 Policy A2.2 Procedures for Biospecimen Access and Utilization PAGE 3 OF 73

4 Chapter 1 Pediatric Heart Network Overview 1.1 Background The Pediatric Heart Network (PHN) is a cooperative program of Clinical Centers, Data Coordinating Center (DCC), and independent Protocol Chair and PHN (Network) Chair, funded by the National Heart, Lung, and Blood Institute (NHLBI) beginning in September 2001 through the cooperative agreement award mechanism. The PHN was established by NHLBI in recognition of the major barriers to clinical studies in pediatric heart disease, including the heterogeneity of conditions, the small numbers of patients with a particular malformation or condition at any one center, differences in treatment approaches among centers, absence of systematic centralized databases, and lack of resources and infrastructure to provide national coordination of collaborative efforts. NHLBI networks have proven to be an effective, flexible way to study adequate numbers of patients with uncommon diseases through a common infrastructure for recruiting, monitoring, and following patients. Networks also provide a platform to train junior investigators in pediatric clinical research, and serve as a vehicle for translational research. The PHN cannot answer all scientific questions pertaining to pediatric heart disease, but many important clinical problems can be addressed within its structure. Studies undertaken to date and their associated publications can be found at the PHN s public web site. 1.2 PHN Mission Statement The mission of the PHN is to improve health outcomes in patients with pediatric acquired and congenital heart disease; disseminate collaborative findings as the basis for improved evidence-based treatment options and standards of care; train and educate new investigators, and provide support and advocacy for families during the conduct of excellent, ethical clinical research. 1.3 PHN Organization The organization structure of the PHN is shown in Figure 1.1. The roles of the collaborative components shown in this Figure are explained in this Chapter and in Chapter PHN Chair NHLBI has the discretion to appoint a PHN (Network) Chair, who would typically not be affiliated with any of the core clinical centers. The PHN Chair would serve as the Chair for all Steering and Executive Committee calls and meetings, and oversee the functions and conduct of the Executive and Steering Committees. With the DCC Principal Investigators PAGE 4 OF 73

5 (PIs) and the NHLBI Project Scientists, the PHN Chair would contribute to overall guidance for the PHN., and work with the Protocol Chair and clinical center investigators to develop clinical research protocols PHN Protocol Chair NHLBI has the discretion to appoint a PHN Protocol Chair. The Protocol Chair is appointed by the NHLBI and is not affiliated with any of the core clinical centers. The Protocol Chair provides overall guidance for the selection and development of new Network studies and works with clinical center investigators to develop clinical research protocols. The Protocol Chair is eligible to participate in Study and Writing Committees Clinical Centers Clinical Centers are selected to participate in the PHN after rigorous peer review, and meet the minimum requirements for participation. These include appropriate experience and expertise to conduct clinical studies in congenital and acquired pediatric heart disease, an established research program, and demonstrated access to a sufficient number of patients to accomplish their portion of the proposed protocols. Clinical Centers must be dedicated to the standards of the PHN and demonstrate an ability to cooperate with other PHN centers in collaborative research. NHLBI expects that PHN Clinical Centers will participate in all studies. During the proposal process, Clinical Center PIs are expected to discuss potential studies extensively with the relevant personnel at their centers to determine feasibility. Any serious issues with feasibility should be discussed with other members of the Study Committee and Steering/Executive Committees as necessary, and may be a basis for determining that a study is not feasible in the PHN. Only when it has been determined that a proposed study is feasible at all PHN sites will it be considered for formal development as a study protocol. In the rare event that a study is considered to be high priority, but a clinical center is unable to participate, NHLBI will consider this on a case-by-case basis, and determine how to proceed. If the study is implemented, it is likely that financial penalties in the form of reduced core costs would be incurred by the non-participating clinical center. Every Center s progress and contribution to PHN studies is reviewed annually by NHLBI. If any Center is consistently unable to contribute to PHN studies, their participation in the PHN may be terminated before the end of the five-year grant period. A Clinical Center may consist of a consortium of sites, referred to as a main site and subsites. The main site is responsible for 1) disbursement of per-patient reimbursement funds to other members of the consortium (the sub-sites); 2) ensuring that all consortium members have resources to attend required study protocol trainings; and 3) making certain that the sub-site investigators and staff participate in required network conference calls (e.g., SC, Nurse Coordinator, and Protocol Committee calls). A sub-site may participate in all PHN studies or selected studies, as is deemed appropriate by the Clinical Center PI. The enrollment contribution of all institutional members of the consortium contributes towards the enrollment target of the Clinical Center. a. Principal Investigator Responsibilities Clinical Center PIs bear the overall responsibility for their Center s participation and performance in the PHN. To provide the expertise required to direct a PHN Clinical PAGE 5 OF 73

6 Center, the PI must be a pediatric cardiologist. The PI appoints all co-investigators, hires and supervises key personnel, ensures the ethical conduct of research, and represents the Clinical Center on the Executive and Steering Committees. The PI or designee is responsible for contributing to the development of new protocols, analyses and publications, monitoring the conduct of PHN studies, monitoring data collection, and ensuring adherence to quality assurance measures. This requires that mechanisms be in place at each Clinical Center to promote both formal and informal communication among all PHN study staff. NHLBI will assess the adequacy of these mechanisms during site visits. The PI is responsible for ensuring that the necessary financial arrangements, Institutional Review Board (IRB) approvals, and federal assurances are in place before participation in each study. Each center PI should have a plan for training new investigators. In addition, the PI is ultimately responsible for all regulatory and reporting requirements. b. Change in Status of a Principal Investigator If a PI leaves the institution or is not able to continue to provide the appropriate time and effort to direct the Center, another PI must be designated when there is no official multiple PI plan or when the PI is only one of two in a multiple PI plan. The NHLBI program office must approve all replacements. The current PI must submit a letter to the NHLBI program office, countersigned by the local business official, outlining the justification for the individual recommended to replace the PI, and should include that individual s NIH Biosketch and statement of other support. The new PI should meet the requirements outlined in the RFA for the current funding cycle, and have adequate time to devote to PHN studies. Ideally, this individual would already have PHN experience as a co-investigator. c. Co-Investigators Co-Investigators play an important role in PHN activities. Co-Investigators can serve as the chair of a PHN study, as the local PI of a PHN study, on protocol development committees and writing committees, and on standing PHN committees such as the Publications, Ancillary Studies, and Finance Committees. To the extent permitted by travel budgets, co-investigators are expected to attend Steering Committee meetings and they always plan to participate in relevant conference calls. d. Study Coordinators Research Study Coordinators are research nurses or other individuals with comparable experience responsible for ensuring the successful conduct and coordination of PHN protocols under the direction of the PIs. Coordinators are responsible for the day-to-day management of PHN studies, including maintenance of the Center's PHN and protocol files and ensuring adequate staffing, equipment, and supplies to support the needs of PHN studies implemented at the Clinical Center. Coordinators, together with the PIs, set up staff training systems and establish procedures to facilitate recruitment, to ensure adherence to protocols, and to assure the highest standards of protocol implementation, data collection and reporting. Study Coordinators have a significant role in determining the feasibility and estimated cost of study protocols at a given center. Study Coordinators also participate in protocol development, implementation, and abstract and manuscript PAGE 6 OF 73

7 writing committees as members of study committees, and can also propose ancillary studies. Study Coordinators are expected to attend Steering Committee meetings and other applicable PHN meetings and to participate in relevant conference calls. e. Other Staff The conduct of PHN studies requires a multidisciplinary team of professionals. Other staff members who contribute include clerical staff, research pharmacists, nurses, statistical/clinical trial specialists, physicians in related medical and surgical specialties, and other healthcare professionals. These individuals participate in protocol development and implementation as members of study committees, and in abstract and manuscript writing as appropriate and can also propose ancillary studies Data Coordinating Center The DCC is responsible for scientific leadership in clinical research policies and procedures, study design, data analysis, dissemination of results, data management and quality control, site monitoring, and overall coordination of PHN operations. The DCC is overseen jointly by a PI for Clinical and Statistical Science and a PI of Operations. The PIs have extensive experience in the design, conduct, and management of clinical trials according to Good Clinical Practice principles, and are responsible for the supervision and management of DCC staff to ensure the successful completion of PHN goals. The DCC Medical Co-Investigator advises DCC staff on clinical issues relevant to PHN trials and pediatric heart disease generally. The DCC PI of Clinical and Statistical Science leads the statistical team, collaborates closely with Clinical Center PIs and NHLBI staff on biostatistical issues related to the design, implementation, conduct, and analysis of PHN studies, and has reporting responsibilities to the Data and Safety Monitoring Board (DSMB) and the Protocol Review Committee (PRC). The PI of Operations has fiscal, administrative, and systems oversight of the DCC, coordinates activities performed by the DCC teams for implementation and conduct of PHN studies, and supervises non-statistical project staff, including project managers, data managers, programmers, and administrators. A PI or designee participates in every PHN committee meeting. The DCC is primarily responsible for the following areas: Study Design and Planning The DCC advises and assists PHN investigators regarding study design including defining primary and secondary outcomes and the determination of sample size and randomization schemes. DCC staff assists with protocol development and preparation of study materials, including identifying drug packaging and distribution contractors, identifying core laboratories, completing regulatory requirements, and preparing the final protocol, the manual of operations, and data collection forms for each study. DCC staff train and certify Clinical Center staff in study procedures and the use of the web-based database management system. PAGE 7 OF 73

8 Study Conduct The DCC provides and maintains secure, validated computerized data management systems, with capabilities for distributed and central data entry, editing and reporting of data. DCC staff monitors and reports on data quality, protocol adherence, and recruitment status, providing regular reports to study committees, the Steering Committee, and NHLBI. The DCC oversees subcontracts for any drug distribution facilities, specimen repositories, and core laboratories providing services for PHN studies. DCC staff will attend and assist in the coordination of site visits and other quality assurance activities. Data Analysis The DCC is responsible for all aspects of data analysis in the PHN. The DCC provides statistical consultation in planning manuscripts and ancillary studies, and conducts analyses for all publications and presentations. The DCC also will provide limited access data sets per NHLBI policy, and other limited data sets for defined types of ancillary studies (see Chapter 7). Study data reside centrally at the DCC, which is responsible for complete documentation of the study and archiving of the dataset. Management of Patient Care Funds The DCC is responsible for managing and distributing patient care funds. For each study, a site services agreement is established with each participating site, and patient care funds are distributed by the DCC according to the plan for that study. Communication The DCC is responsible for organizing regular conference calls and meetings of PHN committees, and for distributing all study documents, including meeting minutes, recruitment reports, protocols, manuals and data collection forms. The DCC maintains two web sites. The PHN NERI Connect site, which is passwordprotected, contains official study documents as well as meeting announcements and minutes, and complete contact information for all affiliated investigators and staff participating in the PHN. Materials for DSMB and PRC meetings and for in-person Steering Committee meetings are posted to the administrative web site. A partition of this site, which is further restricted to the medical monitor, DSMB Chair, and NHLBI staff, contains summaries of serious adverse events subject to expedited reporting requirements. The PHN public web site was developed and is maintained jointly by NHLBI and DCC staff. This site contains information for families and physicians, and is updated regularly as new publications are added, and study status changes NHLBI The NHLBI, part of the National Institutes of Health (NIH) and the Department of Health and Human Services (DHHS), supports basic, translational, and clinical research in the areas of heart, lung, blood, and sleep disorders. The PHN is one of several networks funded by the NHLBI to promote collaborative investigation into pressing public health problems. The PAGE 8 OF 73

9 NHLBI Program Office staff consists of the Project Scientist and Deputy Project Scientist for the PHN, the PHN Coordinator, other medical officers, Executive Secretaries for the DSMB and PRC, the NHLBI Biostatistician, the Grants Management Specialist, and other staff as may be assigned. Project Scientist and Deputy Project Scientist The Project Scientist and Deputy Project Scientist are responsible for overall PHN operations, including policy development, implementation and conduct; budget formulation and resource allocation; and procedures for identifying new areas of research. They monitor and ensure the safe and effective execution of the program on a day-to-day basis. The Project Scientists are responsible for assuring the scientific merit as well as ethical performance of the research, including the option to withhold support for a participating center if performance requirements are not met. They may propose topics for data analysis leading to abstracts or papers, may lead or participate in manuscript preparation, and may propose but not lead ancillary studies. Per NHLBI publication policies, Project Scientists cannot be the first or senior author on a main results paper. Executive Secretaries The PHN Program Office, in conjunction with the Office of the NHLBI Director, will appoint Executive Secretaries for the PRC and the DSMB. The Executive Secretaries are responsible for the PRC and DSMB meetings, including monitoring the closed and executive sessions. The Executive Secretaries will contribute to the development of agendas for these meetings and will produce and distribute minutes from the meetings. NHLBI PHN Coordinator The NHLBI PHN Coordinator assists in the day-to-day management of the PHN and facilitates all PHN activities. This includes being an interface for the PHN study coordinators with NHLBI, attending site visits, reviewing all IRB-approved consent forms to insure consistency with NHLBI policy, reviewing adverse events, and assisting in protocol development and budget preparation. This individual may propose topics for data analysis leading to abstracts or papers, may lead or participate in manuscript preparation, and may propose but not lead ancillary studies. NHLBI Biostatistician The NHLBI biostatistician provides statistical support to the Project Scientist and serves as an additional resource for PHN investigators during protocol development and data analysis. The NHLBI statistician attends the Steering Committee, PRC and DSMB meetings as the NHLBI s statistical expert. NHLBI Grants Management Specialist The NHLBI Grants Management Specialist (GMS) serves as an authority in grants management for the PHN. The GMS participates in the development and review of PHN fiscal policies and procedures. In addition, the GMS collaborates closely with the Program Office to develop per-patient reimbursement amounts for PHN protocols, reviews progress prior to issuing annual awards and periodic adjustments PAGE 9 OF 73

10 to awards, such as carrying funds forward from one fiscal year to the next. The GMS ensures that award recipients comply with all legal, regulatory and policy requirements, reviews and ensures that all contractual agreements are based on sound business principles, analyzes budgets and funding proposals, negotiates funding levels and terms of award with grantees, and issues finalized grant awards Auxiliary and Affiliate Sites The fundamental structure of the PHN is established through a competitive process of solicitation of applications and peer review. Collaboration with other academic centers is encouraged, however, to foster broader research efforts in pediatric cardiovascular disease. Collaboration can take the form of joining a PHN study as an auxiliary or as an affiliate site, or participating with a PHN investigator on an ancillary study. (The process for participation in ancillary studies is described in detail in Chapter 7 of this Manual.) Auxiliary sites are institutions participating in the PHN because they proposed a study that the PHN decided to conduct, or were added to assist with subject recruitment in a particular study. Auxiliary sites undergo a review of their clinical research experience and infrastructure by NHLBI, the PHN Protocol Chair and the DCC; they are asked to provide data on the number of eligible patients for the particular study at their site, and also to provide detailed information about pertinent imaging capabilities. Only sites that are deemed to be able to participate successfully are invited to do so. Auxiliary sites are added to the PHN under site services agreements with the DCC, which stipulate the payment structure for patients recruited as well as the regulatory requirements that must be met before enrollment can begin. Auxiliary site investigators and staff are encouraged to participate in Steering Committee meetings and calls, and a representative from each auxiliary site is expected to participate in conference calls that relate to the study in which the auxiliary site is participating. Auxiliary site study staff undergoes centralized training for study procedures either at the main training sessions at the beginning of a study, or later in individual sessions with DCC staff if the site does not join at the beginning of a study. Site visits and periodic site status calls are conducted by the DCC and NHLBI as for the Clinical Centers. Affiliate sites are institutions or groups of physicians in practice who collaborate with the PHN by identifying patients who might be eligible for enrollment in a PHN study. A limited amount of screening is done by the Affiliate site and then selected patients are referred to an enrolling PHN site for complete screening. Affiliate site staff are welcome to participate in PHN activities such a monthly study conference calls relevant to the PHN study. A small payment is provided to partially compensate the time and effort involved in patient screening. The participation of Affiliate sites in a PHN study is recognized formally in all study publications. PAGE 10 OF 73

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12 FIGURE 1.1: NETWORK ORGANIZATIONAL OVERVIEW PAGE 12 OF 73

13 Chapter 2 PHN Operational Components The operational components are designed to ensure the smooth functioning of the PHN, and may change from time to time to meet changing needs. 2.1 Steering Committee The Steering Committee includes all participants in the PHN. Steering Committee calls and meetings form the backbone of the PHN, and provide a forum for discussion of all aspects of PHN operations by study staff at all sites. A calendar of meeting dates is available on the PHN NERI Connect site Meeting Structure, Agendas, and Attendance The Steering Committee meets twice a year in person, and has monthly conference calls. Steering Committee calls and meetings are chaired by the DCC PI of Operations and the Protocol Chair, as appropriate, or by the NHLBI Project Scientist in the Chair s absence. The Program Office and the DCC prepare agendas collaboratively. The DCC distributes the agenda to all investigators electronically before each call or meeting. Participation of a representative from each primary PHN site on calls and at meetings is essential to the efficiency and productivity of the PHN. PHN PIs are also encouraged to include fellows and junior faculty in Steering Committee activities as a means of educating the next generation of pediatric cardiovascular clinical investigators. Special consultants and guests may be invited to attend Steering Committee meetings or participate in calls, with the approval of the Program Officer and DCC PIs Minutes Draft meeting minutes are prepared by the DCC within seven working days of Steering Committee calls or meetings, and forwarded to NHLBI and others, as applicable, for comment. Those commenting have four business days in which to respond. The completed minutes are then posted on the PHN website within two and one half weeks of the meeting. 2.2 Executive Committee Formal decision-making for the PHN is vested in the Executive Committee, which consists of the following members: Voting Members o PHN Protocol Chair o DCC PIs (1 vote) o Clinical Center PIs (one representative from each Center) PAGE 13 OF 73

14 o o NHLBI Project Scientists (1 vote) Chair, Study Coordinator Committee Ex officio members o Chair, Publications and Presentations Committee o Chair, Ancillary Studies Committee o Chair, Finance Committee o DCC Co-Investigator o Other NHLBI staff Responsibilities The Executive Committee meets quarterly by conference call or in person. With input from members of the Steering Committee, activities of this Committee include: Setting the overall scientific agenda for the PHN Determining which studies will be conducted Developing PHN policy and procedures Ensuring compliance with PHN policies Determining which auxiliary sites will be added Reviewing study protocols before they are sent to the PRC and DSMB Resolving identified conflicts that affect the conduct of studies or dissemination of results Making recommendations to the NHLBI about major changes in study design if needed Meeting Structure, Agendas, and Attendance The Executive Committee meets in conjunction with all in-person Steering Committee meetings, and holds quarterly conference calls. Executive Committee calls and meetings are chaired by the DCC PI of Operations or the NHLBI Project Scientist. DCC staff circulates a request for agenda items in advance of each meeting. The final agenda is reviewed and approved by the DCC PIs and the NHLBI Project Scientist. The participation of all Executive Committee members is strongly encouraged; if a member cannot participate, an alternate should be designated Minutes Draft meeting minutes are prepared by the DCC PI within seven working days of Executive Committee calls or meetings, and forwarded to the NHLBI Project Scientists, and others, as applicable, for comment. Those commenting have four business days in which to respond. The completed minutes are then posted on the PHN website within two and one half weeks of the meeting. 2.3 Publications and Presentations Committee The primary purpose of the Publications and Presentations Committee (PPC) is to ensure timely preparation of high-quality presentations and publications on behalf of the PHN. The PAGE 14 OF 73

15 PPC reviews all abstracts, presentations and manuscripts in accordance with PHN publication policies (see Chapter 6, Publications and Presentations Policy). The PPC solicits recommendations for policy revisions and presents them to the Executive Committee. The PPC Chair is further responsible for adjudicating any conflicts that arise in writing committees such as inadequate investigator participation or changes in writing committee membership. PPC membership is determined by the PPC Chair, DCC PIs, and NHLBI Project Scientist, and consists of: PPC Chair Protocol Chair A representative from each Clinical Center DCC PI of Statistical Science (or biostatistician designee) DCC Co-Investigator NHLBI Staff (ex officio) Study coordinator Participation of 7 members in any publication review will constitute a quorum. 2.4 Ancillary Studies Committee The primary purpose of the Ancillary Studies Committee (ASC) is to facilitate the conduct of appropriate ancillary studies. The ASC conducts reviews of ancillary study proposals in accordance with PHN policies (see Chapter 7, Ancillary Studies Policy). ASC membership is determined by the DCC PIs and NHLBI Project Scientist, and consists of: ASC Chair A representative from each Clinical Center A representative from the DCC NHLBI Staff (ex officio) Participation of 5 members in any ancillary study review will constitute a quorum. 2.5 Study Coordinators Committee The Study Coordinators Committee consists of the Coordinators from each of the clinical centers, the DCC Project Managers who work closely with the Study Coordinators, and the NHLBI PHN Coordinator. This Committee meets in conjunction with Steering Committee meetings and conducts interim monthly conference calls. The Committee Chair, who is selected from within the group on a periodic basis, is responsible for making a report at each in-person Steering Committee meeting and on some Steering Committee calls. The Study Coordinators Committee reviews the progress of ongoing studies and participates in developing implementation plans for new studies, including the development of patient education materials and other materials as needed. The goal of this Committee is to facilitate sharing of information and collaboration in problem solving on issues related to the day-today conduct of the studies. Topics to be discussed include issues related to the Health Insurance Portability and Accountability Act (HIPAA), IRBs and informed consent; patients concerns; techniques for maximizing recruitment and for optimizing protocol adherence and data quality; and budget and staffing. The Committee may make proposals to the Steering Committee for PHN policy changes or enhancements to improve PHN functioning. The PAGE 15 OF 73

16 Coordinators may also propose topics for PHN protocols, for ancillary studies, or for analysis of existing study data for the purpose of abstracts and peer-reviewed publications. 2.6 Finance Committee The Finance Committee was formed during the second grant cycle to provide systematic input into study budgets, to assist in framing overall PHN fiscal priorities, and to help investigate the costs of pediatric research. The mission of the Finance Committee is to provide timely financial information about individual study costs and the overall PHN budget to assist in planning and prioritizing PHN activities. In addition, the Committee will use information obtained from PHN studies to help estimate the true costs of pediatric cardiovascular research. Members of this Committee are selected by the Finance Committee Chair, DCC PI of Operations, and NHLBI Project Scientist from among nominees submitted by each PHN Clinical Center. The Committee is chaired by one of the Clinical Center PIs, and includes Clinical Center Investigators, Study Coordinators, and budget staff; the DCC PI of Operations, and NHLBI staff. The Finance Committee meets at all Steering Committee meetings, conducts quarterly conference calls, and meets more frequently as needed during protocol development. 2.7 Core Laboratory Selection Committee Each protocol may require one or more core laboratories. A standing Core Laboratory Selection Chair will be appointed, and Core Laboratory Selection Committees will be formed to assist in the selection of core laboratories for each PHN protocol (see Section 4.3). The Committee will typically be composed of up to 5 members, including but not limited to representatives from the Study Committee, Finance Committee, Executive Committee and outside experts as required. Nominations will be solicited by the DCC Project Manager. The Committee members will be selected by the Core Lab Selection Chair, in consultation with the Study Chair, the NHLBI Project Officer, and the DCC PIs. The Committee will review responses to the Requests for Proposals (RFPs) prepared by DCC staff. 2.8 Biospecimen Committee The Biospecimen Committee is responsible for oversight of all biospecimens collected and stored during PHN studies. Committee membership includes PHN Investigators with expertise in relevant assays and cardiovascular genetics in addition to study expertise, a DCC Investigator, a representative of the NHLBI Program Office, a member of the Pediatric Cardiac Genomics Consortium, and a member of the Ancillary Studies Committee (ASC) who will serve as the liaison to facilitate ASC review. Review from experts outside the Committee will be obtained as needed. The Committee will review proposals that include use of biospecimens to ensure that the use and testing of these specimens is appropriate. PAGE 16 OF 73

17 Chapter 3 Oversight of PHN Activities 3.1 Introduction The PHN has two oversight committees: the Protocol Review Committee (PRC), and the Data and Safety Monitoring Board (DSMB). Both are established by NHLBI following NHLBI policy, and consist of individuals with no close professional relationships to PHN investigators. PRC and DSMB members make recommendations to the Director, NHLBI concerning the initiation and conduct of research protocols in the PHN. Members of the PHN PRC and DSMB have expertise in pediatric cardiology, pediatric cardiac surgery, pharmacology, clinical trials design and analysis, ethics, genetics, and other specialties as needed. One layperson serves on the DSMB. A complete listing of the current members of the PRC and DSMB is on the PHN administrative website. 3.2 Protocol Review Committee The PRC is appointed by, and responsible to, the NHLBI to provide independent scientific peer review for protocols developed by PHN investigators. The membership of the PRC includes a chairperson and scientists with expertise in the areas enumerated above. Additional experts are added on an ad hoc basis if necessary to evaluate protocols. The PRC will assess the scientific merit of each protocol based on: Importance of the question to be addressed; Need for a multi-center design to meet objectives; Merit of experimental design; Availability of adequate resources, including medications or devices; Adequacy of patient population and number of patients, including appropriate representation of minorities and women; Appropriate recruitment strategies. PRC meetings are held when protocols require review. When members cannot attend the meeting, they are expected to submit written comments to the Chair 24 hours before the meeting. Input from 3/4 of the members is considered a quorum. At that session, the Study Committee chair presents an overview of the protocol to the PRC members, and answers questions. A discussion period follows, with the PHN investigator(s), DCC staff, and NHLBI staff available to answer questions. When the PRC is ready to conduct an Executive Session, everyone except the PRC members and the PRC Executive Secretary is excused from the session. After the PRC members have formulated their recommendations, PHN investigators and NHLBI staff return to the session to hear the recommendations and to ask and respond to questions as needed. The minutes, which incorporate key concerns and a summary of the recommendations, are prepared by the Executive Secretary, and sent to the PAGE 17 OF 73

18 PRC Chair for review. The final minutes are sent to the Office of the Director, NHLBI for review and approval, and are then distributed by the DCC. 3.3 Data & Safety Monitoring Board The primary objective of the DSMB is to ensure the safety of study subjects and to provide NHLBI with advice on the ethical and safe conduct of PHN studies. When the DSMB meets, participation of 4 members, one a biostatistician, is considered a quorum. The DSMB advises NHLBI on study design, data quality and analysis, and ethical and human subject aspects of studies. The DSMB reviews all ongoing trials and studies, newly developed protocols after PRC approval has been obtained and before study implementation, and all protocol amendments. The DSMB also reviews all ancillary study proposals after review by the Ancillary Studies Committee is complete, and once outside funding, if required, is assured. A full discussion of the role and responsibilities of the PHN DSMB is found in the DSMB Charter. Minutes of each meeting are prepared by the Executive Secretary, and sent to the DSMB Chair for review. Final minutes with the DSMB s recommendations are submitted for review and approval to the Office of the Director, NHLBI. After approval, they are distributed to the DCC. Reports to IRBs: Because this DSMB is convened to supervise multi-center studies, the NHLBI program office will prepare a memo documenting Board recommendations and submit it to the relevant study chair(s) and DCC within 21 days of each meeting. The DCC will forward the memo to each participating research site. It is expected that all sites and the DCC will forward the memo to their IRB. If the DSMB does not identify any safety or other protocol-related concerns the NHLBI Program Office will prepare a Summary Report stating that: a review of outcome data, adverse events, and information relating to study performance (e.g., data timeliness, completeness, and quality) across all centers took place on a given date; the observed frequency of adverse events did not exceed what was expected and indicated in the informed consent; a review of recent literature relevant to the research took place and; the DSMB recommended that the study continue without modification of the protocol or informed consent. If concerns are identified, the report to the clinical centers will outline the concerns, the DSMB s discussion of the concerns, and the basis for any recommendations that the DSMB has made in response to the concerns Medical Monitor(s) As part of the overall data and safety monitoring plan, the PHN established the position of Medical Monitor, whose services are retained through the DCC. NHLBI has the discretion of appointing one or more as needed. This individual is independent of any PHN site, and is selected by NHLBI based on clinical and research expertise in pediatric cardiovascular disease. The Medical Monitor reviews all serious adverse events, and consults the Chair of PAGE 18 OF 73

19 the DSMB for additional input as needed. The Medical Monitor also advises the PHN on strategies for improving adverse event reporting. PAGE 19 OF 73

20 Chapter 4 Protocol Development and Implementation 4.1 Study Proposals Development of research concepts is an integral part of the PHN as this process introduces innovative topics for collaborative research and stimulates intellectual discussion concerning the direction and scope of patient care. The NHLBI Project Scientist and the PHN Protocol Chair can provide guidance regarding the general nature of topics appropriate for investigation by PHN. In addition to standard studies involving all PHN Clinical Centers, we will also consider proposals for pilot studies. The purpose of a pilot study is to collect preliminary data for and/or to determine feasibility of a fully-developed study. In contrast to standard PHN studies, there is no expectation that all PHN sites will participate in pilot studies. A sufficient number of subjects should be available for recruitment within a reasonable time period from the proposed participating centers. If practice variation or certain feasibility issues are being assessed in a pilot study, then including centers with differing practices will strengthen the proposal. The PHN proposing investigator and Center principal investigator will be responsible for ensuring that all PHN policies concerning proposals are followed. A PHN investigator who proposes a study should always consult with the Center principal investigator. A non-phn investigator who proposes a study must work with a PHN Center investigator to bring the proposal forward. Consultation with the Center principal investigator is also recommended. Investigators should also seek guidance from the PHN Protocol Chair, the NHLBI Project Scientist, and/or the DCC PI of Statistical Science as this will facilitate understanding of whether the proposed study fits into PHN goals Sources of Study Proposals New ideas for collaborative research emerge from formal and informal discussion among PHN investigators, the Nursing Research Committee, and from outside investigators who wish to propose an idea for the PHN s consideration. Proposals may include studies that will require funding by the PHN, those that are supported by PHN nursing research funds, or studies (Section 4.1.2) that have other sources of partial or full funding (see Section 4.1.3). If not involved as an investigator, the Center principal investigator should review proposals before submission to the the Data Coordinating Center (DCC) Proposals for PHN-funded Studies The proposal process starts with triage of the proposed study by PHN leadership. This can be done with a proposal or a one-page synopsis as described in Section a. The steps are depicted in Figure 4.1. PAGE 20 OF 73

21 FIGURE 4.1. DEVELOPMENT OF NEW STUDIES a. Format Proposal A proposal should not exceed 10 pages (11 pt Arial), excluding title page and references, and include the following: 1. Abstract: Include abrief summary with the primary hypothesis and research question(s). 2. Study Aims and Hypotheses: State the Primary Aim and all Secondary Aims, with any hypothesis(es) and study outcomes for each Aim. 3. Background: Include prior studies, rationale for study, and brief rationale for study outcomes. PAGE 21 OF 73

22 4. Study/Trial Design: Include a brief overview, possibly a study schematic diagram, procedures to minimize bias if relevant, measures for all outcomes, and a schedule of measurements and visits. 5. Selection of Subjects: Include inclusion and exclusion criteria; data regarding subject availability; and an estimate of the accrual period. List participating institutions for pilot studies and collaborating institutions, if relevant. 6. Treatments: If applicable, describe the treatments to be administered. Treatments can include drugs, biologics, surgery, devices or diagnostic procedures. Describe the regulatory (FDA) status of the proposed treatment, if applicable. 7. Safety Considerations and Assessments 8. Statistics: Include a sample size calculation as well as a preliminary analysis plan. For Phase III trials, calculate sample sizes based on a minimum of 85% power. Assumptions used for the calculation of target sample size should be provided, including but not limited to the Type I and II error rates, magnitude of treatment crossover, the detectable effect size, and inflation for loss to follow-up, incomplete evaluation, and interim looks at the data. 9. Limitations 10. Budget: Include a general description of budget items and an estimate of the costs. 11. Disclosures: Include disclosure of any significant financial interest(s) that might be related to the proposed area of research. 12. References One-Page Synopsis An optional initial step is a one-page synopsis to be reviewed by PHN leadership to determine if the proposed study is appropriate for PHN before a proposal is prepared. Involvement of a PHN Center investigator is not necessary at this step but consultation with the PHN Protocol Chair, the NHLBI Project Scientist, the DCC PI of Statistical Science and/or other PHN investigators may be helpful. The synopsis should include the study aims, hypotheses or research questions, and a brief description of study design and population, study duration, and a rough estimate of total study costs. If approved by PHN leadership, the next step is development of a proposal as described above. The proposal must be reviewed and approved by PHN leadership before proceeding to SC presentation. Grant application At the discretion of PHN leadership, proposals already in the format for a grant application may be submitted for review in the format required by the granting entity. b. Review and Prioritization Process Scientific merit, relevance and importance of topic, and feasibility are always considered when reviewing study proposals. Each proposal is ranked according to the following criteria: Scientific merit: overall design; meaningful, valid endpoints; reliable measurements PAGE 22 OF 73

23 Relevance and importance of topic: potential impact on morbidity and mortality; degree of controversy in the field; public health importance Feasibility: o Ability to identify a clinically relevant and feasible primary study endpoint, o Willingness among PHN investigators to accept random assignment of patients to the proposed treatments (if a trial is proposed), o Availability of supplier support for study drugs or devices, if applicable, o Likelihood that patient populations of sufficient size will be available within the PHN, and o Cost of proposed study and availability of adequate funds for study conduct. All new study proposals are first triaged by the PHN leadership considering the above criteria. Approved proposals are presented to the Steering Committee (SC) to familiarize the PHN with the proposal and to permit preliminary discussion. The discussion will focus on identification of a primary study endpoint, significance, investigator equipoise about the research question proposed for study, and numbers of potential subjects available. Details of the study design such as specific inclusion and exclusion criteria, measurement schedule, and secondary endpoints will be considered but may change during full protocol development. At any point during the review of study proposals, PHN leadership may ask for written answers to specific questions posed to the lead writer of the study proposal, input from the Finance Committee, detailed reviews of clinical center databases to assess subject availability, consultation from outside experts in the field, and/or any other information deemed necessary for complete review. All such information will be submitted to the DCC for distribution to the Executive Committee (EC) and to the lead writer of the study proposal. At the discretion of PHN leadership, interim votes may be taken by the EC to assess interest in further review of any proposal. After SC review of a study proposal, the EC will discuss it. During this discussion, the EC member from the proposer s site will be excused. After the meeting, members will be provided with a confidential electronic ballot and asked to vote on whether the proposal should move on to the next stage of development and to provide comments. The vote and comments should reflect a consensus opinion of the clinical site voting, not just the view of the site EC member. The PI of a Center proposing a new study must abstain from voting on that proposed study. However, all Center PIs can vote on proposals related to current PHN studies even if from the Center proposing the study. If a proposal receives a majority of NO votes, the proposal will not progress to the next stage of development regardless of priority ranking. The lead writer of the study proposal will receive aggregate feedback from the DCC on the voting results. The aggregate feedback will be prepared by the Protocol Chair. Development of protocols is prioritized based on ranking after the voting and will depend on current PHN resources. The EC may recommend resubmission of a revised proposal. A letter (2-page maximum length) describing the revisions made in response to the specific review comments or questions should accompany the revised proposal. PAGE 23 OF 73

24 c. Study Committee Formation After the EC votes to pursue development of a protocol, or after external funding is received for a study, a Study Committee is formed. The PHN Protocol Chair, the DCC PIs, and the NHLBI Project Scientist will select the Study Committee chair and co-chair (if indicated). This is a prominent position within the PHN, and requires a considerable investment of time and energy. The Chair usually will be the individual who proposed the study. In the case of a non-phn investigator, the Committee will always be co-chaired by a PHN investigator who will take responsibility for ensuring that study implementation complies with PHN policies and procedures. The DCC will solicit nominations for membership on each Study Committee from the participating clinical sites. Final membership will be determined by the Committee Chair and the Protocol Chair, and will typically consist of: At least one representative from each participating clinical site, More than one representative from each site may be appropriate if additional expertise is required, At least one clinical research pharmacologist for any study involving drugs, At least one Study Coordinator, A statistician and Protocol Lead from the DCC, Core laboratory directors or designees for the proposed study if defined, and NHLBI staff. For studies where PHN partners with pharmaceutical or other outside sponsors, a representative from the relevant sponsor may also participate in the study committee as an ex officio, non-voting member. Once a Study Committee is formed and approved, calls will be scheduled by the DCC to occur at least monthly during protocol development and during the study. The Study Committee Chair assumes leadership responsibility, but must work collaboratively with the other members of the Committee. These responsibilities include working with the DCC to convene meetings and conference calls and monitoring the overall progress of the protocol and the study. Minutes of each call and meeting are prepared by DCC staff, approved by the Committee Chair, and then distributed via and posted on the PHN administrative web site. The primary objectives of the Study Committee are to: Produce a concept protocol (see Section 4.2.2), if necessary, for review by the PRC, Write the full study protocol, consent forms, and appendices, Modify protocols as recommended by the SC, PRC, and DSMB, Assist the DCC with information necessary to develop the manual of operations, Prepare data collection forms, Assist the DCC with details of drug donation, formulation and distribution, as required, Assist the DCC in obtaining equipment and supplies, specifications for core laboratories, and other logistics necessary to begin the study, Create study materials for patients, including study brochures and study closeout letters, Create materials and presentations for sites to use in publicizing the study locally, PAGE 24 OF 73

25 Monitor implementation, conduct, and performance of the study in conjunction with the DCC and NHLBI, Advise the Steering and Executive Committees, via the PHN Protocol Chair, DCC, or NHLBI, about special problems or concerns that arise during study implementation or conduct and that may require protocol amendment, Prepare abstracts, make presentations and write manuscripts on the primary and major secondary study results, and Conduct other activities to disseminate study findings widely. The importance of having each site (PHN and auxiliary) participate in the Study Committee The importance of having each site (PHN and auxiliary) participate in the Study Committee calls cannot be overstated. These calls allow investigators to share problems and concerns, and learn from others about effective solutions. They also facilitate standardization of protocol conduct while the study is underway. For these reasons, attendance will be taken on each call. The PIs from each Clinical Center will be responsible for ensuring that their Center is represented during and contributes to all Committee activities. If, in the opinion of the Committee, a Committee member is not participating fully, that member will be replaced with another investigator from the Clinical Center in question. Committee members who do not actively participate will be replaced at the discretion of the Study Chair; the Study Chair will be replaced by the EC. The Study Committee can invite non-phn investigators from PHN Clinical Centers, or in special circumstances from outside clinical centers, to assist in the protocol development process when special expertise is required or the need for additional centers for a specific protocol is anticipated. If the PHN agrees to add auxiliary centers for a study, representatives of centers identified during the protocol development process are expected to work on the Study Committee with PHN investigators to develop the protocol. Once a study is approved by the DSMB, additional auxiliary sites and core laboratories can be added to the Study Committee as needed. Non-PHN investigators will be considered full members of the Study Committee, and may participate in any votes that are taken on the Committee. Partners in specific protocols, such as foundations or industry, will not participate in Committee activities, but will be provided with regular updates on study progress Proposals for Studies Funded by non-phn Funds Grant applications for outside funding for follow-up studies or new studies are encouraged. The primary consideration during PHN review of these proposals is whether the PHN would be interested in and be able to conduct the protocol if outside funding were obtained. Investigators proposing to apply for outside funding for follow-up or new studies should be either PHN investigators or include a PHN co-investigator. a. Synopsis for Initial Screening PAGE 25 OF 73

26 Interested investigators should prepare a synopsis as described in Section 4.1.2a, with the addition of a brief statement identifying the source of funding being sought, for review by the PHN leadership. If approved, and the synopsis is a follow-up study to an ongoing or completed PHN study, the synopsis must then be submitted for discussion to the relevant Study Committee via to the Study Chair. If the Study Committee review is favorable, the grant application is submitted to the EC for review as described below. If the synopsis is not involving a follow-up study, then a grant application is submitted to the EC for review after approval of the synopsis by PHN leadership. Initial screening will take about 3 weeks. b. Grant Application for Full Review If the synopsis is reviewed favorably, the applicant(s) will be asked to submit a draft grant application or comparable information to the EC for formal review. This process will take days. The EC will assign two reviewers from among SC members. Reviewers will not be from the same institution as the applicant(s) or have other conflicts of interest. At the same time, the proposal will be sent to the Finance Committee for review. At the next convenient SC meeting or call, the applicant(s) will be invited to present the proposal, the reviewers will present their reviews, and the SC will discuss the proposal with Finance Committee input. After the SC discussion and Finance Committee input, the EC will vote by secret ballot. If the application is from a Core Center, the Center PI is recused from voting on that proposal. The Protocol Chair will notify the applicant(s) of the decision. If the vote is favorable, a letter in PDF format on PHN letterhead from the Protocol Chair indicating PHN support for the proposal will be provided to the applicant(s) to include in the grant application. c. Reconsideration of Proposals If a grant application is not funded and a revised application is planned, the applicant must notify the Protocol Chair at least 6 weeks before the next grant submission date. The EC will conduct an expedited review (at the next scheduled meeting or electronically) of the proposal to determine if the study is still a priority for the PHN. The decision will be conveyed to the applicant(s) by the NHLBI Project Scientist. If favorable, a letter will be provided to the applicant(s) to include in the grant application. 4.2 Protocol Development and Review Study Protocol Formats Two protocol formats have been defined: the concept protocol and the full study protocol. The format for each new study proposal approved by the EC will be determined by PHN leadership. In general, proposals for fairly well-developed studies from outside investigators, straightforward studies, and follow-up studies will be developed immediately into a full study protocol. Less well-defined proposals will generally be first developed into a concept protocol. The concept protocol is typically 8-12 pages long and focuses only on scientific background, rationale for the study, the primary endpoint, and feasibility of recruitment and study execution. The PRC may recommend to the NHLBI that the protocol not be developed PAGE 26 OF 73

27 further. If the concept protocol is accepted, then the PRC feedback provides the PHN investigators with valuable advice to help guide final protocol development. This approach hopefully will avoid the PHN having a fully developed study protocol rejected, an outcome that is inefficient and detrimental to group morale. Note that the DSMB does not review concept protocols Preparation of the Study Protocol Development of the study protocol, whether a concept protocol or the full study protocol is a large task that requires great effort on the part of many PHN members. Authorship of sections of the protocol is a collaborative effort by the Study Committee, led by the study chair. The framework of the protocol document is a function of a protocol template provided by the DCC and should reflect the most recent protocol developed by the PHN. The Study Committee is expected to work out major protocol issues, and to present the results of these discussions to the SC during regularly scheduled SC calls and meetings. The Study Committee should obtain input from relevant core lab personnel. The Study Committee also may form specialized subgroup committees for the duration of protocol development, which focus on areas such as core lab/imaging or neurodevelopmental assessment. Any materials that the Study Committee wants to discuss with the SC should be provided in a timely fashion to the DCC to be distributed as background materials for the pertinent call or meeting. Estimates of available potential subjects are critical to both concept and full study protocols. The statistical representative from the DCC provides preliminary sample size calculations based on any available data early in the process, possibly even during EC review of the study proposal. Feasibility estimates are also done based on availability of subjects as reported by the clinical centers. As the primary outcome, analysis, and inclusion and exclusion criteria sections of the protocol become more defined, these estimates are refined and updated Planning for Protocol Review The completed protocol must be approved by vote of the Study Committee, which must be documented in the Study Committee meeting minutes. The protocol must be prepared in final formatted form before review can take place. As the Study Committee approaches this endpoint, scheduling of review meetings by the PRC and DSMB should take place. The length of time between EC, PRC and DSMB review must be estimated and will depend in part on the complexity of the proposal. A timeline for each protocol should be developed in collaboration with the Study Chair, DCC personnel, Protocol Chair, and NHLBI personnel Formatting Requirements The PI who is submitting the protocol should work with DCC personnel to get the protocol as close to a final version as possible. The protocol should be single-spaced, in 11 point font. PAGE 27 OF 73

28 The DCC will prepare final formatting including placing the version number and version date in the footer and on the title page, preparing the table of contents, and assuring that the protocol is free of split tables and images. The study PI should make sure to give the DCC at least two business days to format the final protocol before submission to the EC Cover Letters A cover letter for the PRC should be prepared before submission to the EC and submitted to the EC for review with the protocol. The purpose of the cover letter is to introduce the broad concept of the study to the reviewers and to discuss any design issues that do not fit conveniently into the protocol document (e.g. choice of primary outcome, why there is no placebo group, etc). Statements about details of the protocol that are readily available in the protocol document should NOT be repeated in the letter. In general the letter should be no longer than 3 pages- the shorter the better. Examples of cover letters for PRC review are available on the PHN NERI Connect home page under Network Policies and Templates, at the following link: %20Year%2011/Network%20Policies/PRC%20cover%20letter%20examples.pdf. Once the protocol has been approved by the PRC, a new cover letter should be prepared for submission with the protocol to DSMB. The letter can be exactly the same as that submitted to the PRC with an additional paragraph added towards the end as follows: The PHN Protocol Review Committee met on {date}, and voted unanimously to approve the protocol. A copy of minutes of this meeting is enclosed for your review. The PHN has the following responses to the PRC s recommendations: recommended that.. Examples of cover letters for DSMB review are available on the PHN NERI Connect home page under Network Policies and Templates, at the following link: %20Year%2011/Network%20Policies/DSMB%20CoverLetters%20examples.pdf Protocol Review by the EC Both concept and full study protocols are reviewed by the EC before being submitted to the PRC. Protocols are sent to the EC 14 days before votes are due. Protocols are sent to the entire EC, but only voting members provide approval/disapproval and comments. The votes PAGE 28 OF 73

29 and comments are submitted to the Protocol Chair who will prepare the final EC review within 5 days. As described below (Sections and ), in the event of PRC or DSMB disapproval of a protocol, the EC will re-review the revised protocol prior to resubmission to the disapproving body. This re-review typically will be handled electronically, and the review time may be less than 14 days Preparation of Presentation Slides Slides to be used when presenting the protocol to the PRC and DSMB via conference calls should be prepared by the Study PI in collaboration with the Study Committee and Protocol Chair. In general, you should have no more than slides as the PRC and DSMB members have all read the protocol. Examples of PRC and DSMB slide sets are available on the PHN NERI Connect home page under Network Policies and Templates, at the links below. PRC Slide Set Examples: %20Year%2011/Network%20Policies/PRC%20Slide%20Set%20Examples% pdf DSMB Slide Set Examples: %20Year%2011/Network%20Policies/DSMB%20Slide%20Set%20Examples% pdf A version that has been approved by the Study Committee should be sent to the Protocol Chair at least one week before the PRC call. After review is completed, these slides are posted on the PHN Neri Connect website 3 days before the call. Statistical analysis is obviously included as part of the slide set; whether the Study PI or the DCC statistician presents these slides is up to the people involved. The slides for the DSMB conference call can be essentially the same as those for the PRC call with the addition of 1-2 slides as needed to review PRC recommendations. A version that has been approved by the Study Committee should be sent to the Protocol Chair at least one week before the DSMB call Protocol Review by the PRC This conference call can occur 7 to 8 weeks after the protocol has been submitted to the EC. The final version of the concept (if applicable) or full study protocol is submitted to the PRC for review, with a cover letter outlining the key issues prepared by the study PI and the Protocol Chair. If a concept protocol was reviewed by the PRC, the cover letter for the full study protocol should include responses to PRC comments about the concept protocol. See Chapter 3.2 for further information about the conduct of the PRC meeting. If the PRC does not approve a concept (if applicable) or a full study protocol, this likely means that major substantive revisions are required. Therefore, review and approval of the revised protocol by the EC is required prior to submission to and re-consideration by the PRC. The PAGE 29 OF 73

30 need for re-review can be waived in the rare circumstance that it is not considered necessary by the PHN Leadership and the Protocol Chair Preparation of Case Report Forms (CRFs) This is a demanding task that requires meticulous attention to detail and involves close collaboration between Committee members and DCC staff. The Committee is encouraged to obtain input from relevant core lab personnel Budget The study budget should be developed while the protocol is being prepared. This is a collaborative effort between the DCC, applicable PHN investigators, and NHLBI staff. A budget is developed for each study to include the costs of any patient care or diagnostic testing that are not part of routine clinical care, drug costs if applicable, costs to cover the study-related expenses of patients and families, and similar items. A final estimated budget with site cost estimates should be submitted to the EC along with the study protocol and to the Finance Committee. The Finance Committee and the NHLBI program office review the spreadsheets and develop an average per-patient cost that will be applied to all PHN sites. In the case of auxiliary sites participating in only a single protocol, the per-patient budget can include a small amount for infrastructure expenses, such as study coordinator time. The per-patient budget will be posted on the PHN Web Site DSMB Review After PRC review and NHLBI approval, any recommended changes are addressed, and the protocol is submitted to the DSMB for review accompanied by a cover letter that includes a summary of changes recommended by the PRC (see section above) and draft Informed Consent and Assent Forms. The Study Chair prepares a PowerPoint presentation with input from Study Committee members and network leadership to assist in presenting the study during the DSMB meeting (see section above). See Chapter 3.3 for further information about the conduct of the DSMB meeting. If the DSMB does not approve a study protocol, this may mean that major substantive revisions are required. Review and approval of the revised protocol by the EC is required prior to submission to and re-consideration by the DSMB. The need for re-review can be waived in the rare circumstance that it is not considered necessary by the PHN Leadership and the Protocol Chair. 4.3 Study Implementation After approval by the PRC and DSMB, the DCC circulates a timeline for pre-recruitment activities, and final arrangements are made for any necessary supplies or services, such as study drug manufacture, special equipment or diagnostic testing. Selection of any auxiliary (including international) sites occurs at this time through a formalized application and vetting process. After final revision, draft CRFs are distributed to Study Coordinators at 2-4 clinical centers for pilot testing using existing patient charts. The Coordinators return detailed comments (but not the completed CRFs) to the DCC on a standardized feedback form. After revisions are PAGE 30 OF 73

31 made in response to the piloting feedback, the CRFs are finalized and the complete CRF set, along with a standardized Form Approval Signoff form is sent to the Study Chair, the PHN Protocol Chair (if appropriate), the DCC PI of Statistical Science and one or two additional members of the Study Committee. After signed approval of the CRFs is received, Study Committee members work with the DCC to provide relevant validation ranges for study data fields and to develop detailed definitions of data fields for inclusion in the study Manual of Operations. The DCC also uses this information to write form specifications which are provided to programming for the development and testing of the web-based data management system and randomization system (if applicable). After the DSMB approves a protocol and revisions to that protocol are made based on their recommendations, a Request for Proposals (RFP) for any new Core Lab(s) necessary for the study is distributed to the PI at each center. The Study Chair and other members of the Study Committee will provide input to the DCC on scientific details and selection criteria to be included in the RFPs. PHN clinical centers may apply to be a core laboratory as long as the proposed core laboratory director is not the center or study PI (unless the study is research stemming from core laboratory activities). If there are no applicants or no applicants with sufficient expertise and facilities, then the RFP is distributed to outside parties. The typical deadline for submission of proposals is six weeks after an RFP is distributed. Submitted proposals are reviewed by Core Laboratory Selection Committee members, which may include outside expert technical consultants if necessary. All reviewers use a standardized rating form that assigns points in the areas of facilities and equipment; managerial coordination plans; qualification, experience, and availability of proposed personnel; and ability to perform testing and quality control procedures. If none of the submitted proposals is deemed acceptable, then the RFP will be re-competed by posting on academic/commercial websites. After selection of a core laboratory based on the reviewer scores and budgetary considerations, the Core Laboratory Selection Committee Chair communicates the results of the review to applicants IRB/REB Approval After DSMB approval, the final protocol and patient-related materials including any modifications requested by the DSMB are distributed by the DCC to all participating clinical centers for local IRB submission. IRB/REB approval of the protocol and related documentation (e.g., patient education materials, study brochures, questionnaires, HIPAA forms) is required before recruitment can begin. PIs may need to devote time to educating the IRB/REB Chair about the need for consistency in study documents for multi-center studies to avoid unnecessary editing of consent forms and other study materials. NHLBI policy requires that all consent forms in multi-center studies be reviewed by the DCC and/or the NHLBI program office before submission to the local IRB and again after IRB/REB approval to ensure that required content has not been revised incorrectly. Approved consent forms are posted to a password-protected web site for review by DCC and NHLBI staff Training and Certification One or more training sessions are held for the Study Coordinators and research staff. These sessions are coordinated and conducted by the DCC. Before the study is started, each center must complete certification requirements, which include demonstration of familiarity with study procedures, methods for endpoint measurement, use of the database PAGE 31 OF 73

32 management system, and designation of staff to conduct the study. The DCC will work with each center on certification and notify NHLBI when it is achieved. Certifications are issued following successful completion of a database system training exercise, successful demonstration of randomization processes and completion of a post-protocol training quiz. In addition, dedicating training sessions are held, as applicable, for technical echo/imaging site staff, developmental specialists, and for pharmacists Study Registration All PHN studies will be registered with ClinicalTrials.gov to fulfill journal requirements for subsequent publication and to meet FDAAA requirements. The DCC will work with NHLBI to oversee this process. PAGE 32 OF 73

33 Chapter 5 Quality Assurance 5.1 Overview A number of measures have been established to assure standard administration of all study protocols and procedures by all data collectors across all PHN sites; these range from weekly editing of the data by the DCC to on-site visits by NHLBI and DCC staff to review and evaluate research procedures and organization. Several routine reports are generated and distributed to the Steering Committee by the DCC that report the quality of study procedures and data. 5.2 Routine Study and Data Quality Checks Data management activities that the DCC performs to maintain data integrity and quality include: 1. A system check to identify data forms not completed within the specified study windows. If a data form is not completed within its window, then the form is considered overdue. The window is defined specifically for each protocol. 2. A system check to identify data fields that have pending validation edits or missing values and data discrepancies. Monitoring of these edits is done by rerunning the report until no edits are produced. Validation edits identify missing or incongruent information within and across data fields. These edits are provided in real-time to the clinical site at the time of data entry. DCC checks on outstanding edits are additionally conducted on a periodic basis to notify sites of any backlogs. Clinical sites are routinely notified and requested to review and take action on items identified per the above procedures. In addition, a Quality Control Double Data Entry (QC DDE) process is established for each study to help ensure accurate data entry and to alert the DCC of high levels of discrepancies in data entry. Approximately 5% of data entry forms entered into the data management system are randomly selected to be re-keyed. The QC DDE system uses a self-adjusting algorithm to select an additional percentage of forms for double data entry when a data entry person fails to maintain an acceptable error rate. The system also blocks data entry when QC DDE is not completed in a timely manner. 5.3 Protocol Training The DCC provides training at study start up to study staff based on their role. Anyone performing randomization procedures will receive randomization training (i.e., study coordinators, PIs), anyone working with the database will receive database system training, PAGE 33 OF 73

34 and all study coordinators and a designated center investigator will receive and must successfully complete protocol training. The DCC monitors the clinical sites adherence to randomization and protocol procedures and violations and deviations from the protocol, including enrollment of ineligible patients, which are reported to the Steering Committee at least quarterly. The DCC also monitors recruitment for all PHN studies. Recruitment reports emphasize the numbers recruited per month by clinical center, the numbers screened, and the numbers eligible and consenting. These reports are submitted to the SC and study committees. 5.4 Site Visits Clinical Centers Clinical Center site visits are evaluations conducted by the DCC and NHLBI staff, and additional PHN representatives if needed. Site visits occur in person at least once during each protocol, and additional site visit conference calls may be scheduled. Site Initiation Calls or Visits The purpose of a site initiation conference call or visit is to ensure that sites are initiating protocols effectively, to help with any procedural issues, and to share information learned at other sites. Site initiation calls are used primarily for auxiliary sites that may not be familiar with PHN procedures, but also may be conducted at all sites for a particularly complex protocol. They are scheduled by the DCC in conjunction with NHLBI. A standard agenda is provided to each site prior to the call, and the site PI is asked to review staffing and procedures for the protocol. If concerns are identified, a follow-up call or visit may be needed. Quality Assurance Site Visits The purpose of a quality assurance site visit is to: Review PHN procedures with the clinical center s PI and relevant staff, Assess the clinical center s proficiency in executing PHN protocols, Assess data quality and completeness, Provide consultation in identifying and solving problems, and Transfer effective approaches from one clinical center to others. Considerable detail and planning are undertaken to conduct a site visit. The clinical site PI will be contacted in advance to set up a suitable date. The DCC and NHLBI will establish a specific Site Visit Agenda in conjunction with site investigators; the Agenda will be distributed to the clinical center before the site visit. During a quality assurance site visit, the team will evaluate the following areas: Overall performance of the clinical center and the conduct of PHN protocols, including ability to meet enrollment targets, Data quality, to include a chart audit of select data variables, Regulatory documentation, Facilities and records, PAGE 34 OF 73

35 Research procedures and organization, Pharmacy (if applicable), and Any PHN Core Laboratories at that particular clinical center. Site Visit Objectives and Procedures The site visit will be conducted in accordance with the following objectives and procedures. Some of these procedures, such as touring the facilities, will only be required at the first site visit: a. Research Setting: Staff and Facilities Objectives o Evaluate adequacy of facilities o Evaluate adequacy of staffing in relation to required tasks to conduct PHN protocols Procedures o Walking tour of the facilities, including: clinic space, offices, data entry site(s), files, pharmacy, echo lab, MRI suite, and other areas as applicable o Meet study personnel, including the principal investigator, study coordinators, pharmacists, data entry personnel, grants management administrator, and other staff involved with the conduct of PHN protocols. b. Organizational Procedures and Study Administration Objectives o Evaluate communication among research staff o Evaluate staff training o Evaluate organization, maintenance and security of subject research records o Evaluate organization and process of data collection Procedures o Review established methods of communication among clinical site investigators and staff o Review maintenance and storage of regulatory documentation and official PHN correspondence (Operations Memos) o Assess organization and process of data collection, transmission, and storage by reviewing subject research record organization, methods and maintenance c. Regulatory Review Objectives o Evaluate regulatory binder for completeness consistent with good clinical practice guidance. o Evaluate completeness and dates of informed consents Procedures o Review completeness of regulatory binders PAGE 35 OF 73

36 o Review the informed consent of every randomized patient for signatures and dates to ensure the documents were current and within the IRB approval window d. Trial/Study Patients: Data Quality & Protocol Compliance Objectives o Evaluate site-specific procedures for protocol implementation o Evaluate completeness of study documentation o Evaluate accuracy of records o Evaluate accuracy and completeness of adverse event reporting o Evaluate accuracy and completion of data collection and recording o Evaluate delays responding to data edits and form completion Procedures o Review completeness of screening and actual vs. expected enrollment numbers o Review a sample of randomized patient medical records for accuracy and completeness of adverse event reporting o Review eligibility violations, loss to follow-up, and protocol violations o Review randomization procedures, location and maintenance of back-up randomization materials, pharmacy records, completeness of pharmacy drug log and comparison of drug log with patient chart. (If applicable) o Review charts requested for chart audit. The DCC will identify patient charts to be audited in advance. The clinical center should prepare for this audit by providing the required charts and ensuring that the charts and protocol study nurses and coordinators are available for the site visit team. Charts will be examined for agreement between medical record and submitted PHN data for key study outcomes, eligibility, and treatment variables. Additional review occurs to identify a signed copy of the informed consent, data completion procedures, and protocol violations o Review timeliness of data entry, data transmission, and response to and documentation of date. o Review quality of screening/randomization logs and mail-in data forms Oral and Written Recommendations The site visit team will convey an assessment of the site with regard to the objectives outlined above at the end of the visit. Areas of excellence as well as any recommendations for improvement will be noted. In addition, a formal written report will be prepared for the site PI by NHLBI and the DCC, and forwarded to the center following the site visit. The written report will detail the site visit team s overall assessment of the clinical center with specific emphasis on problem areas. The written report will provide a formal assessment of the following areas: Research Setting: Staff and Facilities Organizational Procedures and Study Administration Data Management Adverse Event Reporting Trial/Study Patients: Data Quality Summary of Recommendations PAGE 36 OF 73

37 The Center PI will have 10 days to challenge any item in the report. If significant concerns are noted, the site PI will be asked to reply in writing, usually within 30 days. In this case, a follow-up site call will be scheduled within 3-6 months Data Coordinating Center Site visits will be conducted by NHLBI to the DCC at least once in each grant cycle. The purpose of such visits initially is for NHLBI staff to become familiar with DCC staff and processes. On subsequent site visits, the purposes may include resolving problems, refining PHN procedures, and other issues. The verbal and written reporting format will be similar to those used for the Clinical Center site visits Site Visits To Address Problems (audit) Site visits to clinical centers can be initiated by NHLBI if concerns arise about ability to recruit, adherence to the protocol, data quality, or patient safety. The purpose of such a site visit is to assess reasons for the problems identified, and to work together to develop a plan to improve performance. The site visit team may include additional members depending on the nature of the problem, and the site principal investigator may be asked to include additional personnel, including Division and Department chairs. At the conclusion of this type of site visit, a verbal report will be provided, with a formal written report to follow, focusing on problem areas and recommended solutions. A written response to the recommendations, with a timeline for implementing them, will be required from the clinical site within 30 days of receipt of the NHLBI formal written report. Site visits to the DCC can be initiated by NHLBI if concerns arise about the ability to provide appropriate support to PHN studies. The purpose of such a site visit is to assess reasons for the problems identified, and to work together to develop a plan to improve performance. The site visit team will include NHLBI staff, and may include senior investigators from other data coordinating centers or contract research organizations. A verbal report will be provided at the end of the site visit, and a written report focusing on problem areas and recommended solutions will follow. A written response will be required from the DCC within 30 days of receipt of the NHLBI formal written report. 5.5 Performance Reports Clinical Center Reports Performance reports will give Clinical Centers and the NHLBI an objective measure of performance. They will be generated periodically and will be available to NHLBI peer reviewers upon re-competition of the PHN. Evaluation will focus on overall Center participation in PHN activities, and for each study protocol will consider: Recruitment Protocol Adherence Study Completion Data Quality Timeliness of data entry PAGE 37 OF 73

38 Citizenship DCC Reports Performance reports will give the DCC and NHLBI an objective measure of performance at the DCC. A tool developed by NHLBI is used to solicit input about the performance of the DCC from the Clinical Center PIs and Study Coordinators in the following areas, including timeliness of DCC responses: Staff and administrative operations Organization and conduct of site visits, conference calls and meetings Protocol development, training, and forms development Data management and statistics Summary scores as well as detailed comments are generated and provided to the DCC, usually before a site visit by NHLBI staff. 5.6 Unblinding Procedures for Trials Request for Unblinding Unblinding of individual patient treatment assignment during the conduct of the overall trial has the potential to introduce bias into screening procedures and determination of trial endpoints for future and currently enrolled patients. A request for unblinding of treatment assignment should only be made in situations where knowledge of the treatment assignment will actually affect the subsequent care or decision-making process for care of the trial subject. Typically such a request is made in a rare life-threatening situation or where the outcome of the index event prompting the need for unblinding has other permanent consequences. However, such situations do not always require knowledge of the treatment assignment to provide proper care. In some instances, holding study drug administration for a short period of time may be sufficient to assess patient condition and response to cessation of study drug as an alternative to unblinding. It should be assumed that the trial subject will remain in the trial if study visits are not yet completed and will continue adherence to the trial protocol after the event is resolved. Therefore, every effort should be made to maintain trial participation in a blinded nature Initial Steps 1. All considerations of unblinding should be discussed in detail with the PHN clinical center PI before a formal request is made, and the PI should assess whether the situation truly requires an official unblinding request. 2. The primary 24-hour verbal contact for an unblinding request is the Trial Chair. Contact information for the trial chair for each active study can be found on the PHN Administrative web site 3. The request for unblinding of treatment assignment must also be made in writing to the Trial Chair and to the DCC PI of Statistical Science by the PHN clinical center PI, or that center s designee. PAGE 38 OF 73

39 5.6.3 Permissions 1. Permission/acknowledgement for unblinding will be provided in writing by the Trial Chair (or designee) or the DCC. Whenever possible, contact of the local pharmacist should not occur prior to receipt of permission. Rare life-threatening or emergency situations In rare life-threatening or emergency situations, patient welfare may necessitate unblinding before the PHN Trial Chair or DCC can be contacted for discussion. In such cases, the local pharmacist for medication trials, or the provider with knowledge of the study intervention administered for other trials should be contacted per local guidelines, but ideally only after full discussion with the PHN center PI. Such unblinding that occurs without PHN Trial Chair or DCC involvement should be reported the first working day after the event Procedures 1. After receiving written permission for unblinding, the treatment assignment should be obtained from the local pharmacist for medication trials, or the provider with knowledge of the study intervention administered for other trials. 2. The assignment information should be provided only to the physician who is directly responsible for the care of the subject to resolve the index event. The treatment assignment should not be revealed to trial staff or specialists unless critical to the decision-making process of care. The number of persons to whom the treatment assignment is revealed should be kept to a minimum, regardless of involvement in the PHN trial. 3. If the approved unblinding request is for a patient who has completed all trial requirements/study visits, the local pharmacist (or, for a non-drug trial, the appropriate provider) should provide the treatment assignment in writing to the primary cardiologist (who may be part of or outside the PHN clinical center) and send a copy of the letter to the DCC PI with the patient s identifying information omitted. Documentation Considerations The treatment assignment should not be recorded in the research record or study file of the subject. In addition, if possible, the recording of information regarding treatment assignment in the medical record should occur only after/if the subject withdraws completely from the trial (due to death or request of the family/physician) and the conduct of the entire trial is completed. Every effort should be made to separate the recording of information regarding treatment assignment in the medical record from the research records and files. Communication Considerations If unblinding is considered necessary after a patient has completed the trial, it is the responsibility of the PHN clinical center PI or investigator involved in the care of the patient to speak directly with the primary cardiologist to request that physician notes forwarded to the PHN center avoid reference to the patient s actual treatment received during the period of time that the trial is ongoing. PAGE 39 OF 73

40 Post Trial Completion Unblinding Unblinding guidelines apply equally to patients who have completed all trial requirements/study visits while the study is still active. At the end of all patient follow-up for the trial for all enrolled patients, treatment assignments will be provided to Clinical Center PIs by the DCC. PAGE 40 OF 73

41 Chapter 6 Publications and Presentations Policy 6.1 Introduction The PHN undertakes unique scientific investigations impacting knowledge of the pediatric cardiology patient population and its care. Because of the great effort that goes into PHN studies and the large amount of resources used, study investigators have the right and responsibility to communicate their findings to the scientific community and to the public at large. To minimize the possibility of inaccurate data in published materials, it is the policy of the PHN that all data and text considered for all papers, abstracts, and materials for presentation at scientific meetings be submitted to the Publications and Presentations (PPC) Committee for review and approval prior to presentation or publication. Also, the DCC shall review these materials to verify that they are accurate and consistent with data used in other PHN documents and papers. PHN centers are not permitted to write papers on local data and experience related to PHN protocols. Investigators may lead or join a writing committee to prepare a manuscript on a topic of interest using data from the entire study. 6.2 Objectives The objectives of the PHN Publications and Presentations policy are: 1. To ensure orderly and timely dissemination of all pertinent data resulting from PHN studies; 2. To ensure the scientific accuracy of PHN presentations and papers; 3. To ensure that all investigators, particularly those of junior rank, have the opportunity to participate and be recognized in PHN presentations and publications; 4. To ensure that press releases, interviews, presentations, and publications of PHN materials are accurate and objective, and do not compromise the scientific integrity of these collaborative studies; 5. To establish procedures which allow the PHN PPC and Executive Committee (EC) and the NHLBI to exercise review responsibility in a timely fashion for PHN publications and presentations; and 6. To maintain a complete up-to-date list of PHN presentations and publications, and to make this information readily available to all PHN investigators and the PHN DSMB. PAGE 41 OF 73

42 6.3 Definitions Main Papers and Presentations Main papers and presentations are those reporting results dealing with the main hypotheses of the PHN study (e.g., primary and secondary endpoints, the design of the study) as well as papers and presentations using the complete study data set. In general, main papers and presentations refer to use of study data from all sites Other Papers and Presentations Other papers and presentations are those not encompassed by the above category. Examples include those related to work done in ancillary studies or by a single center or a limited number of centers (i.e., using data from a subset of all the sites), or papers related to PHN operations Content 1. PHN study design, screening and baseline data may be used for preparation of abstracts and presentations prior to the planned end of the study. 2. Observational studies with complete data on an intermediate time point may be used for preparation of abstracts and presentations prior to the planned end of the study, either by agreement of the Study Committee or for Study Aims that were pre-specified in the protocol. 3. With the exceptions listed in points 1 and 2 above, PHN trial data involving randomized patients will not be analyzed for purposes of publication or presentation outside the PHN until the planned end of the study PHN Investigator A PHN investigator is any physician or coordinator at a main or auxiliary clinical center or core lab, or statistician or project manager at the data coordinator center, or NHLBI scientist or coordinator who is involved in conducting a PHN study Quorum All materials and decisions requiring approval by the PPC rather than just the PPC Chair require a quorum of 7 PPC members. In all instances, the waiting period for PPC member response is the stated deadline for the review/decision in question, even if 7 members reply before the deadline. 6.4 Proposal and Approval Process for Papers, Abstracts and Presentations For each PHN study, the Study Committee plays an important role in identifying and prioritizing writing topics for development of papers and abstracts. Although the Study Committee will generate most proposals for abstract and paper topics, any PHN investigator can propose a writing topic to a Study Committee. An overview of the steps in this process is displayed in Figure 6.1. PAGE 42 OF 73

43 FIGURE 6.1 STEPS FOR PREPARATION OF PAPERS The Study Committee is charged with evaluating and prioritizing all proposals for abstracts, presentations, and manuscripts related to the main study. 1. Writing topic proposals must be submitted in writing to the Study Committee Chair. The proposal should clearly state the research question or hypothesis and include a brief background statement to clarify the purpose and importance of the research question using the Writing Topic Proposal Form. 2. Writing Topic Proposals should be written with the understanding that only one paper will be prepared if the proposal is approved (see also #5 below). 3. Writing Topic Proposals should also be written with the understanding that the proposed paper can be completed using the existing study dataset. Although additional measurements may enhance the depth or breadth of a study dataset, priority will be given to writing topics that utilize existing study data, which will facilitate the Network s mission of rapid dissemination of research findings. Additional data collection and system modification requires resources at both the PHN sites and the DCC, and may divert resources from existing studies. Therefore, a strong justification for a request for additional data must be provided. If additional data are essential to a paper topic, then approval is required. The first step is for the request for additional data collection to be reviewed and approved by the Study Committee. If the Study Committee PAGE 43 OF 73

44 agrees, then the proposer must submit a request to the PHN EC using the Request for Additional Study Data form. 4. The Study Committee will review the proposal within the context of other proposed and approved writing topics. If approved, the topic will be prioritized for development. If approved with modifications, the Writing Topic Proposal must be revised before it is sent out for WC member nominations. 5. If, during the course of developing a paper, the Writing Committee (WC) determines that the original topic is best addressed in multiple papers, the WC must choose the specific paper they will write and provide the Study Committee Chair with a brief explanation. The Study Committee Chair will determine the suitability and priority of the chosen subtopic, and has the discretion to involve the Study Committee as a whole in this assessment. Writing Topic Proposals will then need to be developed for topics not included in the chosen paper and these must be submitted, approved, and prioritized following the procedures herein. A WC(s) will be constituted for the approved topic(s) per the procedures in Section In general, an individual should not be Chair of more than one actively working WC at a time. A WC is considered to be actively working from formation until a manuscript is submitted to a journal. With appropriate justification, the PPC Chair will approve exceptions to this rule. 7. The DCC will inform the Study Committee when data analysis for an approved writing topic can begin, and will assign a statistician to the topic. 6.5 Selection of Writing Committee Chair and Members for Papers and Abstracts 1. A WC will be constituted when the DCC indicates that data analysis for a topic can begin within two months. On behalf of the PPC Chair, the DCC will invite nominations from PHN principal investigators at each main and auxiliary site and the DCC, the study chair(s), core lab principal investigators for the study, Protocol Chair, and NHLBI. The Study Coordinator Chair will be similarly notified, and Study Coordinators interested in a writing topic should contact their respective Principal Investigators for consideration of nomination. The PI must provide the rationale for each nominee (such as level of participation in the development or implementation of the study protocol, or the nominee s specialty area of expertise). Most WCs will have one representative from each PHN site. However, in some instances it may be appropriate for a site to nominate more than one representative, and in others none, depending on the topic. A PI can propose more than one nominee, under exceptional circumstances, with appropriate justification. Nominations received by the stated deadline will be forwarded to the PPC Chair and to the Study Chair(s) and copied to the NHLBI and Protocol Chair. 2. In most cases, the proposer of a writing topic will chair the WC. The PPC Chair and WC Chair will determine the membership of the WC. All WCs for main papers, abstracts, and presentations will have DCC representation. Any disagreements about the membership of a WC will be addressed first by the PPC. If resolution is not possible, the matter will be referred to the EC. PAGE 44 OF 73

45 3. It is the intent that selection of WC members is equitable and fair to all groups and individuals participating in this collaborative program, including encouragement of participation by younger professional colleagues and Study Coordinators, with due regard paid to exceptional efforts of groups or individuals. 4. The PPC Chair will send the list of approved WC members to the DCC. The DCC will then notify the members by and send them the PHN Writing Committee Responsibilities and PHN Manuscripts: Key Steps and Milestones. The DCC will post the writing topic, the WC members, and the approved writing topic proposal on the PHN website (see Section 10.8). The final analysis outline will be re-posted once the WC has met and finalized the plan. 6.6 Preparation of Papers The steps listed below should be followed in the preparation of PHN manuscripts Responsibilities of the Writing Committee Chair The Chair of the WC should first review the PHN Publications and Presentations Policy and then should: 1. Contact each WC member and review the specific charge to the WC and the timeline for developing the paper based on PHN Manuscripts: Key Steps and Milestones. 2. Communicate with the WC to develop a detailed manuscript outline, specify research hypotheses, and draft dummy tables. The Writing Topic Proposal form is to be modified by the WC Chair to document all WC decisions. 3. Submit the finalized Data Analysis Request form and dummy tables to the DCC statistician and collaborate with the statistician to identify needed data and analyses. The WC was formed with the knowledge that the DCC is ready to perform needed analyses but all should be aware that the DCC will process all requests for data analysis according to the overall priorities of the PHN as determined by the EC. Analysis requests will be triaged by the DCC PI according to this principle and where necessary, if there are competing priorities across PHN studies, the EC will provide guidance. 4. Assume a leadership role in writing the paper. Obtain input from every member of the WC and make every effort to accommodate the expression of differing interpretations and alternate analyses within the body of the manuscript, so that all points of view are represented to the satisfaction of every member. The WC Chair is responsible for tracking and documenting the contributions of the members of their WC with regard to input provided on all draft documents. 5. Monitor the progress of development of the paper in relation to the PHN Manuscripts: Key Steps and Milestones. Report the status of the paper development to the Study Committee Chair monthly, and present this report on the monthly Study Committee calls. PAGE 45 OF 73

46 6. Communicate with the Study Committee Chair if the WC decides that the original writing proposal is too broad and should be divided into two or more papers rather than the one paper originally approved (see Section 6.4.3). 7. Monitor the participation of the WC members. Members of each WC should participate actively in the writing and review of the paper assigned to that group. The following process will be used for addressing non-performing WC members: a. The WC Chair will first contact the individual directly and indicate concern over lack of participation. Defining this will be at the discretion of the WC Chair but, in general, would include failure to attend WC meetings or conference calls, failure to read and respond substantively to working drafts, and/or repeated failure to meet response deadlines. b. If there is still no or inadequate response from the individual, the WC Chair will notify the Study Committee Chair and the PPC Chair and copy the respective center PI (in the event that the non-performing individual is a center PI, the WC Chair will then instead copy the NHLBI Project Scientist). The center PI (or PPC Chair) will then speak directly with the individual. c. If reasonable participation is still not forthcoming, as determined by the WC Chair in consultation with the Study Committee Chair and PPC Chair, the individual will be removed from the WC and excluded from co-authorship. Whether the center PI can appoint a substitute will be considered on a case by case basis in consultation with the WC Chair and the PPC chair Responsibilities of Writing Committee Members Inclusion on a WC carries responsibilities that must be met in order to be included as an author for the paper or abstract (see Section 6.7). Each WC member is expected to: 1. Participate in all WC conference calls. If unable to attend a call, the member is expected to notify the WC Chair and the DCC and provide input to the Chair before the call. 2. Review the analysis summary before the call. 3. Review all drafts within the stated time frame (typically two weeks) and to provide commentary and/or edits to the WC Chair. If the topic of a conference call is to discuss a draft manuscript, members are expected to have read the manuscript before the call. 4. Review the final draft before its submission to the PPC and submit the approval signoff to the DCC. 5. Voluntarily withdraw from a WC if unable to participate fully in the WC process. This will not preclude future participation in other WCs Responsibilities of the Study Committee Chair The Study Committee Chair is responsible for: 1. Leading the Study Committee in the identification of potential writing topics, followed by approval and prioritization. PAGE 46 OF 73

47 2. Reviewing WC member nominations for appropriateness with the PPC Chair and finalizing the WC. 3. Reviewing the status and progress of approved papers and abstracts in relation to PHN Manuscripts: Key Steps and Milestones on at least a monthly basis. 4. Assist the WC Chair and PPC Chair in addressing non-performing WC members Responsibilities of the PPC Chair The PPC Chair is responsible for: 1. Reviewing WC member nominations for appropriateness with the Study Committee Chair and finalizing the WC. 2. Performing a periodic systematic review of the work of all WCs. 3. Assisting WCs as appropriate or requested. 4. Collaborating with the Study Committee Chair to address non-performance issues related to an individual WC member or the entire WC, including revising the membership or reconstituting the entire WC when indicated. 5. Assisting the DCC in prioritizing work if DCC resources cannot accommodate all simultaneous analysis requests. 6. Summarizing PPC review of abstracts, presentations, and manuscripts, adjudicating PPC comments, and issuing a final PPC decision for approval or disapproval of submission for presentation and/or publication. 6.7 Authorship of Papers and Abstracts 1. For main papers and presentations, the names of members of the WC shall be listed as authors in the masthead, followed by the phrase "for the Pediatric Heart Network Investigators." The WC Chair, with the concurrence of WC members, should determine the order of authorship. The Chair may choose to add PHN investigators to the authorship who are not initially in the WC, with prior approval from the PPC Chair. A major criterion for order of authorship shall be the effort and contribution made by each member of the writing committee in preparation of the manuscript. Membership in a WC without substantive contribution to the manuscript does not justify authorship. In general, "Uniform Requirements for Manuscripts Submitted to Biomedical Journals" (NEJM 1991; 324: ) shall be adhered to with regard to authorship. Disagreement about the order of authors which cannot be resolved by the chair of the WC will be resolved by the PPC Chair or the full PPC if necessary. 2. The list of authors may not be exactly the same on the abstract and corresponding paper. PAGE 47 OF 73

48 3. The phrase "for the Pediatric Heart Network Investigators" added after the names of the authors in the masthead is optional in papers reporting local data, or ancillary studies using local data. 4. Regardless of source of funding, papers produced from ancillary studies must acknowledge the use of PHN subjects in the Methods or Support section of the paper. 5. Acknowledgement of support from the NHLBI and any other sponsors must be included in all PHN papers and presentations. Acknowledge financial support (including the grant number) from the PHN and NHLBI/NIH with the following text: This work was supported by Grant Number(s) from NHLBI and Its contents are solely the responsibility of the authors and do not necessarily represent the official views of NHLBI or NIH. Study-specific text is posted on the PHN website on the home page for each study. 6. Disclosures of significant financial interest must be reported by all authors as required by the journal. 7. A credit roster of all major committees, core laboratories, the DCC, and PHN centers with their members (generally no more than ten persons from each center) is to appear at the end of each main paper (printed as an appendix). Each site PI, the DCC PI, and the NHLBI Project Scientist will be responsible for designating investigators from his/her center who are to be listed in this appendix. It is the responsibility of the DCC to solicit, obtain and prepare the final list for inclusion in each PHN study. 8. If an NHLBI staff member is listed as an author on a PHN manuscript, approval of the manuscript must be obtained by the NHLBI. To expedite approval, it is recommended that the article be submitted simultaneously to the PPC and the NHLBI. 9. If a coauthor of a PHN manuscript has a change in institutional affiliation between the time research was performed and the time of publication, the affiliation of the coauthor will be listed as the institution where the research was performed, regardless of whether the new affiliation is a PHN center. If the first author has a change, then the author's current institutional affiliation and address will be listed separately from the research affiliation section of the title page, for correspondence purposes. 6.8 Clearance and Submission of Papers 1. The final manuscript draft should be submitted to the DCC. The DCC will distribute this to each co-author for review with a form for final electronic sign-off. After this has been accomplished, the DCC will submit the manuscript to the PPC for review, with a specified deadline. 2. Submission to the PPC should be treated as if the manuscript is absolutely ready to be submitted to a journal, so drafts should be clean, with figures labeled appropriately, and references in proper format. 3. Journal requirements for length and other formatting should be followed. PAGE 48 OF 73

49 4. Members of the PPC will prepare comments on the manuscript and a recommendation for approval, modification, or disapproval of the manuscript on the electronic form provided. These forms should be submitted to the DCC and to the WC Chair simultaneously by the deadline. If the WC Chair is simultaneously a member of the PPC, he/she will be recused from participation in PPC decisionmaking related to that manuscript (other members of the WC who are also on the PPC should still participate). 5. The DCC will forward all comments received by the deadline to the PPC Chair. The PPC Chair will prepare a summary letter indicating approval or disapproval, proposing a resolution to any conflicts among reviewers recommendations, and indicating whether PPC review of the revised manuscript is required. This letter will be sent electronically to the DCC. 6. The DCC will then send the summary letter and copies of the comments from individual PPC members electronically to the WC Chair and members. 7. If only minimal revisions (as indicated by the PPC Chair in the summary letter) are requested, the manuscript may be submitted for publication without additional PPC review. A copy of the submitted manuscript should be sent electronically to the DCC and to all co-authors by the WC Chair. 8. If substantial revisions (as indicated by the PPC chair in the summary letter) are required, the revised manuscript will require formal re-approval by the coauthors, and then will be submitted to the DCC for distribution to the PPC for review and approval before submission to the journal. 9. If revisions to a manuscript are requested by a journal, the manuscript will be revised with input from all co-authors, and the co-authors will confirm that they agree with the revisions. The revised manuscript and the letter to the editor will be sent to the DCC and forwarded to the PPC Chair for approval before resubmission to the original journal or to a new journal. If major revisions (with major determined by the PPC Chair) were requested by the journal, the PPC will review the manuscript again. 10. If responses to published commentary are requested by a journal editor, the WC Chair will prepare and distribute the document to coauthors and PPC Chair for review with cc: to the DCC. The WC Chair will determine authorship of the commentary based on contributions, journal requirements/limitations, subject matter, and time frame. Distribution and documentation of published commentary will follow step number 10 above. 11. Since all circumstances that might cause disagreement among PHN investigators on the content and conclusions of a given paper cannot be foreseen, these disagreements will be resolved by the PPC. If resolution is not possible within the PPC, the matter will be referred to the EC. 6.9 Submission of Manuscripts to Pub Med Central When a manuscript is accepted for publication, it must be submitted to the National Library of Medicine s Pub Med Central as required by the NIH Public Access Policy. 1. The lead author is responsible for submission of any manuscript arising from a project with direct funds from NIH to the National Library of Medicine s PubMed PAGE 49 OF 73

50 Central. Assistance from the DCC with the submission process is available; however, the final responsibility for submission remains with the lead author. 2. Prior to submitting a manuscript to a journal, the lead author must ensure that all agreements with the journal publisher permit: 1) submission of the accepted manuscript to Pub Med Central; and 2) archiving the manuscript in the PHN central repository. 3. When a manuscript has been accepted for publication, the lead author must submit the manuscript to Pub Med Central using the NIH Manuscript Submission System (NIHMS). A final manuscript includes manuscript revisions resulting from the peer review but not necessarily copyediting changes from the publisher. This submission fulfills the requirement to submit a copy of a publication with a grant progress report. 4. The lead author should indicate when the manuscript should be made public, i.e., from publication date to 12 months later. 5. If the manuscript is accepted by a journal that submits all NIH-funded final published articles to Pub Med Central, then no further action is required by the lead author. Journals that do this are listed at 6. The lead author should send the initial NIHMS ID and then the PMCID to the DCC. When preparing an application, proposal, or progress report, papers that resulted from NIH funding must be cited by including the Pub Med Central reference number (PMCID) at the end of the citation. When a PMCID is not yet available, then include the NIH Manuscript Submission System reference number (NIHMS ID) and state "PMC journal -- in process". a. Note: PubMed (PM ID) and PMC (PMC ID) numbers are different numbers Preparation, Submission, and Presentation of Abstracts at National and International Meetings The PHN website contains a current list of all relevant meetings and their deadlines for submission of abstracts, including but not limited to the American Heart Association, the American College of Cardiology, the American Academy of Pediatrics, the American Society of Echocardiography, the Society for Pediatric Research, World Congress of Pediatric Cardiology, Heart Rhythm Society, and the Society for Clinical Trials. 1. Abstracts should be prepared only with the prior approval of the corresponding Study Committee Chair. Abstracts involving PHN process or other more general topics not limited to a single study should instead be discussed with the PPC Chair. 2. With rare exception, abstracts must be based on a manuscript already under development in a previously convened WC, and will be prepared by that WC. The Study Committee will give priority to abstracts based on manuscripts that are near completion. If an abstract proposal does require the formation of a new WC, then the steps for Study Committee approval and WC nomination outlined in Sections should be followed. PAGE 50 OF 73

51 3. In the rare event that a proposed abstract requires formation of a new WC, the proposal must be submitted to the Study Committee and then to the DCC at least 4 months prior to the meeting abstract deadline to guarantee the availability of completed data analyses, the opportunity for WC discussion and interpretation of initial findings, and completion of requests for any secondary analyses.. The initial analyses will be provided to the WC Chair of the abstract at least 7 weeks prior to the abstract deadline. 4. All WC members should have the opportunity to have input into the abstract and must approve the final draft before its submission to the PPC. WC members will be listed as co-authors only if they have reviewed the abstract and accepted authorship prior to the abstract submission deadline. 5. The final abstract must be approved by the PPC before it can be submitted to the meeting organizers for consideration. Completed abstracts and certification of co-author review must be submitted to the PPC at least 10 days prior to the abstract deadline in order to guarantee review and allow time for revision if required by the PPC. Supporting data in the form of tables and graphs should be included if these data are not contained in the abstract. 6. WCs are encouraged to have a first draft of the manuscript available for review by the entire Committee within 12 weeks of presentation of the abstract. 7. Abstracts from ancillary studies must also be approved by the PPC prior to submission to meeting organizers. For an ancillary study using only local data, as determined by the Ancillary Study Committee (ASC, see Chapter 7), permission of the PPC must be obtained before submission of results for presentation or publication if this occurs before publication of the main PHN study results. For all other single-center and multi-center ancillary studies, the ASC will determine the level of PPC review and approval required. If an abstract is submitted without prior PPC approval, and the PPC then disapproves, the author(s) will be required to withdraw that abstract immediately. 8. When an abstract is selected by the organizers for presentation at the meeting, the presentation itself e.g. PowerPoint slides, poster, or other format must also be reviewed and approved in advance by the PPC. Submission of the presentation for PPC review should occur no later than 10 days prior to the meeting date. 9. Presentations should: acknowledge all co-authors and the PHN, include relevant financial disclosures, and acknowledge support from the NHLBI and any other sponsors. Acknowledgement of financial support (including the grant number) from the PHN and NHLBI/NIH should use the following text: This work was supported by Grant Number(s) from NHLBI and Its contents are solely the responsibility of the authors and do not necessarily represent the official views of NHLBI or NIH. Study-specific text is posted on the PHN website on the home page for each study. PAGE 51 OF 73

52 10. Slides or posters which either a) have been reviewed and approved previously and used again for a different presentation or b) have been prepared using only published PHN data do not need to reviewed again by the PPC. Copies of the slides or poster along with a description of the presentation (meeting name, purpose, date) should be sent to the DCC to include in the PHN bibliography. Presentations that include a few slides with published PHN data but do not focus on PHN studies do not have to be reported to the DCC Documentation of Publication Process 1. For each publication, a Checklist will be maintained by the DCC so that adherence to the publication process is documented for each publication. 2. The DCC will document publication status on the PHN website for all PHN publications. The author list and analysis outline for each paper will be posted on the PHN web site. 3. For the SC and Study Committee calls, a summary table of manuscripts under preparation will be provided on a monthly basis PHN Ancillary Studies and Presentations 1. Proposals for ancillary studies are submitted in accordance with the ASC guidelines. The Ancillary Study Application Form is available on the PHN website. 2. For single-center and multi-center ancillary studies using data or biospecimens from the main PHN study, the selection of a WC for ancillary study findings, the preparation and submission of papers, and the submission of abstracts may be required to follow the same PPC guidelines that apply to other PHN papers. The ASC will determine the level of PPC review required and inform the PPC Chair and PI of the requirements Dissemination of Information Dissemination of study results is an important part of the PHN mission. Results can be distributed in manuscripts and abstracts as well as informal talks, articles, interviews, and postings to the PHN public website. When communicating with media representatives about PHN studies it is important to: Emphasize the importance of pediatric research in addition to the significance of the science. Mention the PHN specifically and refer reporters to the PHN public web site. Mention NHLBI and any other applicable funding sources (e.g., National Marfan Foundation, Children s Heart Foundation, FDA). PAGE 52 OF 73

53 1. Prior to abstract presentation, the responsible WC is required to submit a copy of the slides or poster, including tables and graphs, to the PPC for review and approval well in advance of the particular meeting. It is also helpful to submit a copy of the presentation text if available. Templates for slides and posters that include the PHN logo, and the NIH and NHLBI logos are available on the PHN website and should be used for all presentations and on all posters. Each presentation shall be identified as the work of the PHN Study Group, be presented for the PHN Investigators, and acknowledge NHLBI/NIH support. 2. For an ancillary study using only local data, as determined by the ASC as presented in Chapter 7, permission of the PPC must be obtained before submission of results for presentation or publication if this occurs before publication of the main PHN study results. In publications from such studies, the Methods section should specify the site of interpretation of the data, if applicable (local vs. core). These presentations need not use the PHN slide or poster template nor include the phrase "for the PHN Investigators." 3. For presentations or publication of single-center or multi-center ancillary studies using main PHN study data or biospecimens, slides and illustrations prepared by the presenting investigator must be approved by the PPC, if so determined by the ASC. 4. Once a main paper has been presented at a scientific meeting, the slides used should be available to PHN investigators and may be used by them at other scientific meetings. However, any such subsequent presentations that will appear in published form must receive approval from the Study Committee and the PPC prior to the presentation, unless the data in the original paper are already published. This review can be expedited assuming that the same slide set is used. 5. The meeting name, date, and location for all such presentations should be forwarded to the DCC by the presenter to include in the PHN bibliography. 6. In the case of study results scheduled for presentation before an organization issuing press releases, the presenter may submit, for release to the press, the text of the presentation after it has been approved by the PPC. If the presentation is based on a manuscript not yet accepted for publication in a peer-reviewed journal, a sentence must be included on the front page indicating the preliminary nature of the results. 7. Slides that have been used at national or international meetings and illustrations or publications of the main study results must be sent to the DCC for archiving, and will be made available to PHN investigators on the PHN administrative web site by the DCC Invitations to PHN Investigators for Presentation of PHN- RelatedInformation The PHN welcomes opportunities to participate and present reports at national and international scientific meetings. When a member of the PHN receives such an invitation, PHN policies with regard to publications and presentations must be followed. PAGE 53 OF 73

54 1. When a PHN investigator is invited to make a presentation about the PHN and/or its studies at a national or international meeting, the invitation shall be sent to the PPC for review and approval. If the request is relevant to a specific PHN study, the Study Committee Chair should be asked to review and approve the request before it goes to the PPC Chair. 2. The slides for presentation (Powerpoint or other format) must be reviewed and approved by the PPC in advance of the meeting date. Presentations based entirely on previously published PHN data may be approved administratively by the PPC Chair, in consultation with the respective Study Committee Chair(s) if indicated. 3. Any presentation of unpublished PHN data or data not otherwise previously presented must be reviewed and approved by the relevant Study Committee and then by the PPC prior to the date of presentation. The proposer will be required to submit a written proposal to the Study Committee, which will consider the proposal within the context of other proposals and WCs, and prioritize it. The proposal should clearly state the research question or hypothesis and include a brief background statement to clarify the purpose and importance of the question. The standard steps for presenting an abstract will be followed in this case (Section 6.12) 4. Presentations of previously published PHN data by PHN investigators at local meetings (city, state or regional) need no prior clearance by the PPC if the presentation is not to be published. However, all such local presentations must be reviewed and approved by the principal investigator at the center making the presentation. PHN investigators should be encouraged to accept such invitations, and should notify the DCC so the DCC can keep record of these presentations Use of PHN Material for Graduate/Medical Student Theses or Dissertations 1. The PPC will review all requests for use by students of PHN data that are not available in public use datasets. 2. The student requesting PHN data must be associated with an investigator in the PHN study. The PHN investigator shall act as the student's "sponsor" with regard to the data request. 3. Students may not use PHN data if the data related to the PHN study s main paper are in progress or if the PPC deems the data necessary for a future paper. 4. If the PPC recommends approval for the use of the requested data, a review group will be established and will include the student as convener of the group. PAGE 54 OF 73

55 5. In most instances the data will be analyzed by the DCC under the direction of the student with respect to research and analysis aims, and compensation to the DCC must be provided according to the terms of a consulting contract. If the data are to be analyzed by the student directly, the DCC will forward a dataset containing the specific variables required by the proposal. If the student requires significant assistance with handling the data or its analysis, a consulting contract with reimbursement to the DCC will also be required. Independent analysis by the student will be for the purpose of an institutional thesis or dissertation only and not for submission to a journal. 6. The review group will take no action regarding the paper until the student has completed and defended the thesis or dissertation, provided this occurs in a reasonable length of time. (The student's sponsor will be requested to report on the student's progress to the PPC.) 7. The students must include in the completed thesis the following: a. a statement acknowledging the PHN for use of the data; b. a statement indicating that opinions, ideas, and interpretations included in the thesis or dissertations are those of the student alone and not necessarily those of the PHN Investigators. 8. When the thesis or dissertation has been completed as determined by the sponsor, the dissertation review group will proceed to prepare the paper(s) for publication. A WC will be formally constituted and will be composed primarily of the review group members. The student should be given the opportunity to take the lead on the paper. If the research topic becomes a formal Writing Topic for the PHN and it was independently analyzed by the student, then analyses for journal submissions will be repeated and/or confirmed by a DCC statistician. The student will be required to submit his/her analysis program(s) to the DCC. 9. The PHN publication policy will apply to any material published from the thesis or dissertation. 10. The PHN reserves the right to proceed with preparing a paper for publication on the thesis or dissertation topic if, in the view of the PPC, the student has not made reasonable progress on completing the thesis or dissertation. PAGE 55 OF 73

56 PHN Manuscripts: Key Steps and Milestones with Related Maximum Timelines Proposed writing topic or abstract Review and approval by Study Committee. Constitution of a Writing Committee (WC) (3 weeks) Nominations solicited and received (2 weeks); PPC approval and notification to WC chair, Study Committee Chair, Site PIs and other nominators, and members of the WC (1 week after nomination deadline ends); WC chair and members posted on the PHN web site; linked to Manuscript Status Chart. Initial conference call held for WC discussion of analyses to be requested (4 weeks) Initial analysis request (refined Outline document) sent by WC Chair to DCC (1 week) Initial DCC analytic memo(s) to WC (6 weeks) Preparation of manuscript and continuing data analyses. This is an iterative process that can involve multiple steps, including refinement of aims and data analyses, requesting additional data analyses, providing data analyses, collecting new data, redefining data elements, and preparing multiple drafts and revisions. In recognition of the variability in the development process for each manuscript, milestones and timelines are as follows: Date and times for at least 6 months of WC calls for major (design and data) manuscripts scheduled by the DCC (2 weeks); Review of analytic memos by WC via conference call or (3 weeks each); Subsequent analysis requests to DCC (1 week each); Subsequent analyses memos prepared by DCC (4 weeks each); Development of draft manuscript by WC, to be occurring simultaneously with DCC analysis according to the following timeline (NB: Timeline may be shorter for main results papers): Introduction and Methods (8 weeks after formation of WC); Results (no later than 12 weeks after receipt of first analysis memo); Discussion (8 weeks after final analyses received). WC review of drafts and final manuscript: First draft distributed to WC (no later than 8 weeks after receipt of final analysis memos from the DCC); WC discussion of and revisions to each draft (4 weeks); Official co-author sign-off on final draft, followed by submission for PPC review (2 weeks); PPC review and decision PPC review (2 weeks); PPC Chair summarizes comments and communicates with WC (1 week). Submission to journal (2 weeks after receipt of PPC approval) Journal decision PAGE 56 OF 73

57 Paper accepted: WC Chair notifies WC members and the DCC immediately; DCC submission to Pub Med Central (1 week). Revisions required: Revised by WC chair and sent to WC members for review and final sign-off (4 weeks for each revision); Sent to PPC Chair (1 week); Reviewed by PPC Chair (1 week); If PPC Chair feels additional input needed, sent to selected or all PPC members for review (2 weeks); WC Chair incorporates PPC comments with resubmission to journal (2 weeks after PPC Chair approval). PAGE 57 OF 73

58 Checklist for PHN Papers Working Name for Paper: Lead Author: Task Proposal for paper approved by the Study Committee DCC solicits nominations for writing committee and forwards to PPC chair Proposer and PPC form WC and lead writer (Chair) designated DCC notifies all nominated persons and PHN SC of WC membership WC membership posted on PHN website Initial conference call; WC develops consensus regarding tables and data analysis WC Chair submits final Data Analysis Request form and dummy tables to the DCC DCC sends initial analytic memo to WC WC begins writing the paper; data analyses continue All co-authors review at least 2 drafts including the final draft Final draft who will distribute for coauthor sign-off Final draft submitted to PPC for review/approval for submission PPC sends approval/disapproval for submission or request for revisions WC Chair incorporates PPC comments; If major, co-authors, DCC, and PPC review the revised manuscript Co-authors, DCC, and PPC review and approve the revised manuscript resulting from any requested revisions from a journal Upon acceptance during copyright signoff, WC Chair requests journal to forward publication to PubMed Central or paper is submitted directly Accepted publication sent to the DCC, PPC Chair, and all co-authors WC Chair sends NIHMS ID and PubMed Central ID to the DCC Date Accomplished Person Responsible PAGE 58 OF 73

59 Chapter Ancillary Studies Policy 7 Investigators are encouraged to propose and conduct Ancillary Studies, particularly multicenter Ancillary Studies. Such studies will enhance the value of main PHN studies and ensure the continued interest of a diverse group of investigators. They provide an exceptional opportunity for investigators, whether within or outside of the PHN, to conduct additional projects at minimal cost, and with greater feasibility and efficiency. All Ancillary Studies must undergo review by the Ancillary Study Committee (ASC). This is not an administrative review but is aimed at protecting the successful completion of the main study and increasing the likelihood of successful extramural funding of the ancillary study. The review provides a thoughtful critique to address areas of the proposal that are weak, incomplete, or lack sufficient clarity in an effort to improve the application. Approval of the Ancillary Study may be accompanied by a strong Letter of Support from the PHN signed by the ASC Chair and the Data Coordinating Center (DCC) Manager. 7.1 Definitions Ancillary Studies Ancillary Studies are investigations that are not part of a main PHN protocol, but use PHN study participants, biospecimens, or data collected by the PHN. Ancillary Studies should be differentiated from Writing Topics (see Figure 1a). Writing Topics use existing data for additional or secondary analyses to answer specific questions. All data for the proposed Writing Topic have been collected in an established PHN database. No additional data are collected and the proposal does not undergo ASC review. In contrast, an Ancillary Study involves acquisition of additional data, regardless of type or amount that were not collected as part of the main PHN protocol. A proposal that requires additional data to be combined with the existing PHN data is subject to the Ancillary Study review process. Figure 1a: Differentiation of Ancillary Study from Writing Topic PAGE 59 OF 73

60 7.1.2 PHN Investigators A PHN Investigator is any member of the relevant main study team from the DCC, a PHN core center, PHN auxiliary center, or core laboratory. These centers are considered initiating centers Initiating Centers An initiating center is one that has participated in the development of the main study or trial concept and protocol. NHLBI will determine which centers are considered initiating centers. 7.2 Funding Support for Ancillary Studies is not available through PHN grant funds. Additional funding is typically required and can be sought from a variety of sources, including NIH research and career awards, grants from academic institutions, and funding from foundations, granting agencies, institutions, or other private sources. The additional demands on each participating center and study subject must be considered and accounted for in the budget. For example, if a study coordinator must retrieve and submit data, the Ancillary Study budget must address the hours needed to complete these tasks and include appropriate compensation. If support from the PHN DCC or support for an outside DCC is required, the costs must be addressed in the budget and include any fees associated with IRB submission, data use agreements, etc. In addition to the funding needed for study execution, the budget must include funds to support the extraction of requested Main Study data from the DCC. Investigators proposing an Ancillary Study will need to provide a complete and detailed list of the data elements needed for their proposal. An incomplete list of the data elements leads to multiple data export requests and inflates the cost of the data export process. The list should be formatted by the study form name and question number. Study forms are available under the main study on NERIConnect. The formatted list should be sent to the DCC at PHNMailbox@neriscience.com at least 2 weeks prior to finalizing the Ancillary Study budget. If additional PHN DCC services are anticipated to support the proposed Ancillary Study, an additional agreement will be enacted. 7.3 Ancillary Study Philosophy All Ancillary Studies should adhere to the following universal guidelines : 1. The specific aims of an Ancillary Study must not overlap extensively with the goals of ongoing PHN studies and cannot preempt the findings of the main study. 2. The Ancillary Study cannot adversely affect either enrollment of patients into the main PHN studies or performance of testing/procedures required in the main study protocols. Required main study tests/procedures should be completed before tests/procedures are done solely for the purpose of an Ancillary Study. If this is not possible, the investigators of the Ancillary Study must provide justification for the timing of the Ancillary Study tests/procedures and provide a clear plan for minimizing the impact on the main study. PAGE 60 OF 73

61 3. Ancillary Study data associated with clinical trials must never be unblinded before analysis of the main trial results is concluded and the primary results have been published. 4. Centrally interpreted data will be used for all study measures that undergo core laboratory review if more than one center is participating in an Ancillary Study. 5. Approval of the Ancillary Study is granted only for the specific testing and analysis detailed in the proposal. Data provided by the PHN cannot be used for other analyses or testing of additional hypotheses without prior approval from the ASC. 6. Partial support from the PHN must be acknowledged when Ancillary Studies include data collected or testing/procedures done solely for PHN research purposes and supported by NHLBI/NIH funds. 7.4 Proposal Process for Ancillary Studies 1. Any investigator can propose an Ancillary Study to the PHN, but a PHN investigator from an initiating center for the main study must be a co-investigator for every multi-center Ancillary Study. 2. Ancillary Studies that use only local data do not require a PHN co-investigator. 3. Members of the PHN Protocol Review Committee (PRC) or Data and Safety Monitoring Board (DSMB) may not propose Ancillary Studies, although researchers from a division or section different than the one with which the PRC or DSMB member is affiliated may do so. This is to avoid the appearance of a conflict of interest for PRC and DSMB members. 7.5 Application and Review Process for Ancillary Studies 1. If the proposed Ancillary Study is to be part of a grant application, ASC approval must be obtained before the grant is submitted. As delineated below, the anticipated total time from date of submission of the Ancillary Study to the Main Study subcommittee to final approval by the ASC is 8 weeks. Grant deadlines are published well in advance and investigators should address the timeline for the ASC review process early in the grant planning stage. If a Letter of Support (in addition to the ASC approval letter) is requested for the grant application, the Ancillary Study Principal Investigator (PI) should provide a draft of the proposed letter with the ASC application. If the study is approved, the ASC chair and the DCC manager will edit and sign the Letter of Support. 2. Proposals for Ancillary Studies must be submitted in writing to the PHN DCC, using the Ancillary Study Application Form. This form can be accessed in the Policies and Templates section of the PHN Administrative website NERIConnect. Refer to Section 7.9 for addional information for studies requesting biospecimens. NIH Biosketches are required only for the PI and the senior mentor (as appropriate). The preliminary Application Form and accompanying documents (including slides for the presentation to the the Main Study Subcommittee) should be submitted to the DCC at PAGE 61 OF 73

62 The subject line of the should state PHN Ancillary Study Application. 3. The Ancillary Study review process begins with a review by the PHN Main Study Subcommittee (Figure 1b). The preliminary Application Form and slides will be forwarded to the Main Study Subcommittee. The proposal is not accepted for review by the ASC until approval is granted by the Main Study Subcommittee and the Ancillary Study Checklist (see 7.9) is completed. Submission of the final Ancillary Study Application that has been approved by the Main Study subcommittee, the Checklist, and appropriate Biosketch(es) triggers the process for Ancillary Study review. The DCC will track the date of successful completion of each step in the review process. The number of revisions, response time of the investigators, and additional reviews, if any, will affect the length of the review process. PAGE 62 OF 73

63 Figure 1b: Ancillary Study Process 4. Within 2 business days of receipt of the application, the DCC will notify the appropriate Main Study chair(s) via and attach the Ancillary Study Application and/or slide presentation and the Ancillary Study Checklist. The DCC, PAGE 63 OF 73